{"gene":"ITLN1","run_date":"2026-04-28T18:06:54","timeline":{"discoveries":[{"year":2001,"finding":"Human intelectin-1 (hIntL-1/ITLN1) was identified as a secretory glycoprotein that exists as a ~120 kDa homotrimer (three ~40 kDa subunits bridged by disulfide bonds) and binds D-galactofuranosyl residues and D-pentoses in a Ca2+-dependent manner, specifically recognizing bacterial arabinogalactan of Nocardia containing D-galactofuranosyl residues but not mammalian glycans.","method":"Recombinant protein expression, carbohydrate binding assays, native gel electrophoresis, Western blot under reducing/non-reducing conditions, RT-PCR for tissue expression","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — reconstituted recombinant protein with direct binding assays and structural characterization, foundational paper","pmids":["11313366"],"is_preprint":false},{"year":2001,"finding":"ITLN1 was cloned as a human intestinal lactoferrin receptor (LfR); the recombinant protein bound human lactoferrin with an apparent Kd of ~360 nM in a partially Ca2+-dependent manner, appeared as 136 kDa under non-reducing and 34 kDa under reducing conditions (consistent with a disulfide-linked homotetramer/multimer), was GPI-anchored on Caco-2 cells, and its overexpression in Caco-2 cells increased 125I-lactoferrin binding (1.7-fold) and 59Fe-lactoferrin uptake (3.4-fold), implicating it in iron uptake from lactoferrin.","method":"cDNA cloning, baculovirus expression/purification, 125I-lactoferrin binding assays, PI-PLC treatment, transfection into Caco-2 cells, 59Fe uptake assay","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 — reconstituted recombinant receptor, functional binding and iron uptake assays with gain-of-function validation","pmids":["11747454"],"is_preprint":false},{"year":2005,"finding":"Omentin (ITLN1) was identified as a novel visceral fat depot-specific secretory adipokine; recombinant omentin enhanced insulin-stimulated glucose uptake in human subcutaneous (~47%) and omental (~30%) adipocytes in vitro, and increased Akt phosphorylation both in the absence and presence of insulin, indicating it sensitizes adipocytes to insulin signaling through Akt activation.","method":"Recombinant protein treatment of primary human adipocytes, glucose uptake assay, Western blot for p-Akt, EST library sequencing, Northern blot for tissue distribution","journal":"American journal of physiology. Endocrinology and metabolism","confidence":"High","confidence_rationale":"Tier 2 — recombinant protein with direct functional assay (glucose uptake) and molecular readout (Akt phosphorylation) in primary human cells","pmids":["16531507"],"is_preprint":false},{"year":2005,"finding":"ITLN1/omentin gene structure was characterized, its promoter region defined, and sequence comparison revealed 100% identity between omentin and human intelectin-1, establishing these as the same protein. Omentin mRNA expression was found to differ in omental adipose tissue from patients with Crohn's disease, suggesting a role in intestinal barrier defense.","method":"Genomic sequencing, sequence alignment, RT-PCR of adipose tissue from IBD patients","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 3 — sequence/expression analysis establishing protein identity, limited functional follow-up","pmids":["16386808"],"is_preprint":false},{"year":2011,"finding":"Omentin (ITLN1) inhibits TNF-α-induced vascular inflammation in human endothelial cells by activating AMPK (phospho-Thr172) and eNOS (phospho-Ser1177), increasing cGMP levels, and suppressing TNF-α-induced JNK phosphorylation and COX-2 expression; NOS inhibition reversed omentin's anti-inflammatory effect, placing eNOS/NO downstream of AMPK in the omentin signaling pathway.","method":"Recombinant omentin treatment of HUVECs, Western blot for phospho-AMPK/eNOS/JNK, enzyme immunoassay for cGMP, pharmacological inhibitors (NOS inhibitor, JNK inhibitor)","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 2 — recombinant protein with multiple orthogonal readouts (AMPK, eNOS, cGMP, JNK, COX-2) and pathway dissection using inhibitors","pmids":["21514279"],"is_preprint":false},{"year":2011,"finding":"Omentin (ITLN1) promotes endothelial cell survival, differentiation into vascular tube-like structures, and ischemia-induced revascularization in vivo through an Akt→eNOS signaling pathway; AMPK acts upstream of Akt in this cascade, as dominant-negative AMPK reduced omentin-induced Akt phosphorylation; eNOS-knockout mice showed no revascularization response to omentin, confirming eNOS dependence in vivo.","method":"Adenoviral omentin overexpression in mice (limb ischemia model), HUVEC differentiation/survival assays with recombinant omentin, dominant-negative Akt/AMPK constructs, PI3K inhibitor (LY294002), NOS inhibitor, eNOS-knockout mice, Western blot for p-Akt/p-eNOS/p-AMPK","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 — multiple orthogonal methods including genetic knockouts, dominant-negative constructs, pharmacological inhibitors, and in vivo model with mechanistic readouts","pmids":["22081609"],"is_preprint":false},{"year":2012,"finding":"Omentin (ITLN1) exerts anti-inflammatory effects in vascular smooth muscle cells by inhibiting TNF-α-induced superoxide production (NADPH oxidase activity), thereby preventing downstream activation of p38 and JNK kinases and suppression of VCAM-1 expression and monocyte adhesion; antioxidant N-acetyl-L-cysteine mimicked omentin's effect, confirming the ROS-dependent mechanism.","method":"Recombinant omentin treatment of SMCs, Western blot for p-p38/p-JNK/VCAM-1, lucigenin assay for NADPH oxidase activity, p38 and JNK inhibitors (SB203580, SP600125), N-acetyl-L-cysteine, monocyte adhesion assay, ex vivo rat aorta","journal":"European journal of pharmacology","confidence":"High","confidence_rationale":"Tier 2 — recombinant protein with multiple pathway inhibitors and orthogonal assays (biochemical + functional), replicated in ex vivo tissue","pmids":["22554771"],"is_preprint":false},{"year":2014,"finding":"Omentin (ITLN1) protects the myocardium from ischemia/reperfusion injury by suppressing cardiomyocyte apoptosis through both AMPK-dependent and Akt-dependent mechanisms; systemic omentin administration reduced infarct size in mice, and both fat-specific omentin overexpression and recombinant omentin in cultured cardiomyocytes (hypoxia/reoxygenation model) showed reduced apoptosis that was reversed by AMPK or Akt blockade.","method":"Mouse I/R model with systemic omentin injection, fat-specific omentin transgenic mice, cultured cardiomyocyte hypoxia/reoxygenation assay, AMPK and Akt inhibitors, Western blot for p-AMPK/p-Akt, apoptosis assays","journal":"Journal of the American College of Cardiology","confidence":"High","confidence_rationale":"Tier 2 — in vivo model plus in vitro mechanistic dissection with genetic (transgenic) and pharmacological (kinase inhibitors) approaches","pmids":["24768874"],"is_preprint":false},{"year":2015,"finding":"Crystal structure of hIntL-1 (ITLN1) at 1.6 Å resolution complexed with β-D-galactofuranose (β-Galf) revealed that ITLN1 uses a bound calcium ion to coordinate terminal exocyclic 1,2-diol groups of microbial glycans; glycan microarray profiling showed ITLN1 binds exclusively microbial glycan epitopes (β-Galf, D-phosphoglycerol-modified glycans, heptoses, KO, KDO) and not any known human glycan epitopes; Neu5Ac (sialic acid), which also contains an exocyclic 1,2-diol, does not bind due to steric/electronic incompatibility; ITLN1 selectively marks Streptococcus pneumoniae serotypes bearing surface 1,2-diol glycans.","method":"X-ray crystallography (1.6 Å resolution), glycan microarray screening, recombinant protein, bacterial cell binding assays","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 1 — high-resolution crystal structure with ligand, validated by glycan microarray and functional binding studies; independently strong evidence base","pmids":["26148048"],"is_preprint":false},{"year":2020,"finding":"ITLN1 suppresses ovarian cancer cell invasion and proliferation in the omental tumor microenvironment by: (1) inhibiting lactotransferrin-induced MMP1 expression to reduce invasive potential, and (2) inducing a metabolic shift in metastatic ovarian cancer cells; in vivo, ITLN1-treated tumor-bearing mice showed marked decreases in tumor growth rates.","method":"Ovarian cancer cell invasion/proliferation assays, MMP1 expression (Western blot/qRT-PCR), metabolic profiling, in vivo mouse xenograft model with ITLN1 treatment","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2–3 — multiple cellular assays plus in vivo model, but mechanistic pathway linking lactotransferrin→ITLN1→MMP1 relies partly on correlation","pmids":["32669559"],"is_preprint":false},{"year":2021,"finding":"ITLN1 suppresses colorectal carcinoma progression by inhibiting tumor vascularization and myeloid-derived suppressor cell (MDSC) accumulation; mechanistically, ITLN1 suppressed tumor-derived IL-17D via the KEAP1/Nrf2/ROS/IL-17D cascade and CXCL2 via p65 NF-κB/CXCL2 signaling, both dependent on PI3K/AKT/GSK3β; PI3K inhibitor LY294002 reversed these effects; ITLN1 also directly inhibited bone marrow HPC differentiation into MDSCs and NOS2 activity on MDSCs.","method":"Orthotopic and subcutaneous tumor xenografts, bone marrow transplantation (H-2b+YFP+ chimerism), ITLN1 overexpression in CRC cells, PI3K inhibitor, Western blot for KEAP1/Nrf2/NF-κB/AKT/GSK3β pathway components, MDSC functional assays (T cell suppression, NOS2, ROS), ELISA for IL-17D/CXCL2","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal in vivo models (orthotopic, subcutaneous, bone marrow chimera) plus pharmacological inhibition with defined molecular pathway readouts","pmids":["34363021"],"is_preprint":false},{"year":2021,"finding":"The ITLN1 missense variant V109D does not alter glycan binding to β-D-galactofuranose or protein oligomerization, indicating this CD-risk-associated variant is functionally neutral for these core molecular activities; ITLN1 protein in the intestine is goblet-cell derived in humans.","method":"Glycan binding assays with recombinant V109D variant protein, oligomerization assays (native PAGE/SEC), immunohistochemistry/immunofluorescence of intestinal tissue","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 — direct functional testing of variant protein for two specific activities (glycan binding, oligomerization) with appropriate controls","pmids":["34145348"],"is_preprint":false},{"year":2022,"finding":"In C57BL/6 mice, the functional ortholog Itln1 is expressed in Paneth cells (not goblet cells as in humans) of the small intestine; Itln1 knockout mice (hypomorphic allele, ~10,000-fold reduction) showed increased susceptibility to acute DSS-induced colitis but no significant effect on diet-induced obesity in two western-diet models, suggesting Itln1 plays a role in intestinal innate immunity but is not a major determinant of obesity/metabolic phenotype in this model.","method":"Itln1 knockout mouse generation (hypomorphic trapping allele), DSS colitis model (acute and chronic), diet-induced obesity model, Western blot and qRT-PCR for tissue expression, IHC for cell-type localization","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 — genetic knockout with defined in vivo phenotypic readouts in two disease models","pmids":["36072603"],"is_preprint":false},{"year":2008,"finding":"Insulin and glucose dose-dependently decreased omentin-1 (ITLN1) mRNA expression, protein levels, and secretion from omental adipose tissue explants ex vivo; hyperinsulinemic clamp in healthy subjects reduced plasma omentin-1 levels in vivo, establishing negative regulation of ITLN1 by insulin and glucose.","method":"Omental adipose tissue explant culture with insulin/glucose treatment, RT-PCR, Western blot, ELISA, hyperinsulinemic-euglycemic clamp in human subjects","journal":"Diabetes","confidence":"Medium","confidence_rationale":"Tier 2 — ex vivo tissue assays plus in vivo human physiological intervention, multiple readouts (mRNA, protein, secretion)","pmids":["18174521"],"is_preprint":false}],"current_model":"ITLN1/omentin is a secreted, Ca2+-dependent homotrimeric lectin that recognizes exocyclic 1,2-diol groups on microbial-specific glycans (including β-galactofuranose, phosphoglycerol-modified glycans, and bacterial LPS components) but not human glycans, functioning in innate microbial surveillance; as an adipokine (omentin), it enhances insulin-stimulated Akt activation and glucose uptake in adipocytes, promotes endothelial survival and revascularization via AMPK→Akt→eNOS/NO signaling, exerts anti-inflammatory effects in vascular cells by suppressing TNF-α-induced ROS/JNK/p38/VCAM-1 and JNK/COX-2 pathways, protects the myocardium from ischemia/reperfusion injury through AMPK- and Akt-dependent anti-apoptotic mechanisms, and suppresses tumor progression in colorectal and ovarian cancer by inhibiting MMP1 expression, blocking IL-17D and CXCL2 production via KEAP1/Nrf2/ROS and NF-κB/PI3K/AKT/GSK3β cascades, and reducing myeloid-derived suppressor cell accumulation."},"narrative":{"teleology":[{"year":2001,"claim":"Identification of ITLN1 as a Ca²⁺-dependent lectin that selectively recognizes microbial galactofuranose—and simultaneously as a GPI-anchored lactoferrin receptor mediating intestinal iron uptake—established its dual functional identity as both a pattern-recognition molecule and an intestinal receptor.","evidence":"Recombinant protein carbohydrate-binding assays and native gel electrophoresis (lectin function); baculovirus-expressed protein with ¹²⁵I-lactoferrin binding, PI-PLC release, and ⁵⁹Fe uptake in Caco-2 cells (lactoferrin receptor function)","pmids":["11313366","11747454"],"confidence":"High","gaps":["Structural basis for glycan selectivity was unknown","Lactoferrin-receptor function has not been reconciled with lectin activity or confirmed in vivo","Native receptor on intestinal epithelium not characterized at the single-cell level"]},{"year":2005,"claim":"Discovery that omentin (confirmed identical to intelectin-1) is a visceral-fat-derived adipokine that enhances insulin-stimulated glucose uptake via Akt activation reframed ITLN1 as a metabolic signaling molecule beyond its lectin role.","evidence":"Recombinant omentin treatment of primary human adipocytes with glucose uptake assay and p-Akt Western blot; sequence identity confirmation and tissue expression profiling","pmids":["16531507","16386808"],"confidence":"High","gaps":["Cell-surface receptor mediating omentin's metabolic effects was not identified","Whether insulin-sensitizing activity occurs in vivo in humans was untested","Altered expression in Crohn's disease was correlative, not mechanistically dissected"]},{"year":2008,"claim":"Demonstration that insulin and glucose negatively regulate ITLN1 expression and secretion from omental adipose tissue, including in vivo during hyperinsulinemic clamp, established a feedback loop linking metabolic state to ITLN1 levels.","evidence":"Omental adipose explant culture with insulin/glucose dose-response (RT-PCR, Western blot, ELISA) and hyperinsulinemic-euglycemic clamp in human subjects","pmids":["18174521"],"confidence":"Medium","gaps":["Transcription factors mediating insulin/glucose suppression were not defined","Physiological consequence of reduced ITLN1 in hyperinsulinemic states not established causally"]},{"year":2011,"claim":"Pathway dissection in endothelial cells established that ITLN1 activates an AMPK→Akt→eNOS/NO signaling cascade that mediates both anti-inflammatory effects (suppressing TNF-α-induced JNK/COX-2) and pro-angiogenic effects (endothelial survival and revascularization in vivo), with eNOS-knockout mice confirming in vivo eNOS dependence.","evidence":"Recombinant omentin on HUVECs with pharmacological inhibitors and phospho-protein readouts; adenoviral omentin overexpression in mouse limb ischemia model; dominant-negative AMPK/Akt constructs; eNOS-knockout mice","pmids":["21514279","22081609"],"confidence":"High","gaps":["Upstream receptor for ITLN1 on endothelial cells remains unidentified","Whether AMPK activation is direct or requires intermediate kinases was unknown"]},{"year":2012,"claim":"Extension to vascular smooth muscle cells showed ITLN1 suppresses TNF-α-induced inflammation by inhibiting NADPH oxidase-derived superoxide, which prevents downstream p38/JNK activation and VCAM-1 expression, broadening its vascular anti-inflammatory mechanism beyond endothelium.","evidence":"Recombinant omentin on SMCs with lucigenin superoxide assay, pharmacological inhibitors (SB203580, SP600125, NAC), monocyte adhesion assay, and ex vivo rat aorta","pmids":["22554771"],"confidence":"High","gaps":["Direct molecular target of ITLN1 on SMCs not identified","In vivo relevance to atherosclerosis not tested genetically"]},{"year":2014,"claim":"ITLN1 was shown to protect the myocardium from ischemia–reperfusion injury by suppressing cardiomyocyte apoptosis through both AMPK-dependent and Akt-dependent mechanisms, extending its cytoprotective role to cardiac tissue.","evidence":"Mouse I/R model with systemic omentin injection, fat-specific omentin transgenic mice, cardiomyocyte hypoxia/reoxygenation assay, AMPK and Akt inhibitors","pmids":["24768874"],"confidence":"High","gaps":["Whether ITLN1 acts directly on cardiomyocytes or via paracrine intermediates was not resolved","No receptor identified on cardiomyocytes"]},{"year":2015,"claim":"The 1.6 Å crystal structure resolved how ITLN1 achieves microbial selectivity: a single Ca²⁺ ion coordinates terminal exocyclic 1,2-diol groups present on microbial but not human glycans, explaining why Neu5Ac (sialic acid) is excluded despite containing a 1,2-diol, and glycan microarray confirmed exclusive microbial-epitope binding.","evidence":"X-ray crystallography with β-Galf co-crystal, comprehensive glycan microarray, bacterial cell binding assays with S. pneumoniae serotypes","pmids":["26148048"],"confidence":"High","gaps":["No structure in complex with phosphoglycerol or heptose ligands","Downstream signaling triggered upon microbial glycan engagement is unknown","Whether ITLN1 opsonizes bacteria for phagocytosis or directly kills them was untested"]},{"year":2020,"claim":"ITLN1 was shown to suppress ovarian cancer invasion by inhibiting lactotransferrin-induced MMP1 expression and inducing a metabolic shift in metastatic cells, establishing an anti-tumor function in the omental microenvironment.","evidence":"Ovarian cancer invasion/proliferation assays, MMP1 Western blot/qRT-PCR, metabolic profiling, in vivo mouse xenograft model","pmids":["32669559"],"confidence":"Medium","gaps":["Causal link between lactotransferrin, ITLN1, and MMP1 relies partly on correlation","Metabolic shift mechanism not defined at the molecular level","Direct binding of ITLN1 to cancer cells vs. stromal-mediated effects not distinguished"]},{"year":2021,"claim":"Mechanistic dissection of ITLN1's anti-tumor activity in colorectal cancer revealed suppression of MDSC recruitment through dual inhibition of IL-17D (via KEAP1/Nrf2/ROS) and CXCL2 (via NF-κB), both converging on PI3K/AKT/GSK3β; separately, the CD-associated V109D variant was shown to retain normal glycan binding and oligomerization, and mouse Itln1 knockout increased colitis susceptibility without affecting diet-induced obesity.","evidence":"Orthotopic/subcutaneous xenografts with bone marrow chimera, PI3K inhibitor, MDSC functional assays; recombinant V109D protein binding/oligomerization assays; Itln1 knockout mouse DSS colitis and western-diet models","pmids":["34363021","34145348","36072603"],"confidence":"High","gaps":["Whether V109D affects functions beyond glycan binding (e.g. adipokine signaling) is untested","Mouse knockout was hypomorphic (~10,000-fold reduction), not a true null","Receptor mediating ITLN1's PI3K/AKT activation on tumor cells is unknown"]},{"year":null,"claim":"The identity of the cell-surface receptor through which ITLN1 activates AMPK/Akt signaling on endothelial cells, cardiomyocytes, adipocytes, and tumor cells remains entirely unknown, representing the central unresolved question in ITLN1 biology.","evidence":"","pmids":[],"confidence":"Low","gaps":["No receptor has been identified for ITLN1 adipokine/signaling functions","Whether lectin (glycan-binding) and adipokine (signaling) functions use the same or distinct receptors is unknown","Effector mechanisms downstream of microbial glycan recognition (opsonization, complement, direct killing) are uncharacterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[0,8]},{"term_id":"GO:0038024","term_label":"cargo receptor activity","supporting_discovery_ids":[1]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[2,4,5,7,10]},{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[2,4,5,7]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[0,2,8,13]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[4,5,6,7,10]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[9,10]}],"complexes":[],"partners":["LTF","PRKAA1","AKT1","NOS3","NFKB1","NFE2L2","MMP1"],"other_free_text":[]},"mechanistic_narrative":"ITLN1 (intelectin-1/omentin) is a secreted, disulfide-linked homotrimeric lectin that functions in innate microbial surveillance and metabolic/vascular signaling. Its crystal structure reveals a Ca²⁺-coordinated binding site that selectively recognizes exocyclic 1,2-diol groups on microbial glycans—including β-D-galactofuranose, phosphoglycerol-modified glycans, heptoses, and KDO—while excluding all tested human glycan epitopes, enabling discrimination of microbial surfaces such as Streptococcus pneumoniae [PMID:26148048, PMID:11313366]. As a visceral-fat-derived adipokine, ITLN1 enhances insulin-stimulated Akt phosphorylation and glucose uptake in adipocytes [PMID:16531507], promotes endothelial survival and revascularization through an AMPK→Akt→eNOS/NO cascade [PMID:22081609], suppresses TNF-α-induced vascular inflammation by blocking NADPH oxidase-derived ROS and downstream JNK/p38/COX-2 signaling [PMID:21514279, PMID:22554771], and protects the myocardium from ischemia–reperfusion injury via AMPK- and Akt-dependent anti-apoptotic mechanisms [PMID:24768874]. ITLN1 also suppresses colorectal and ovarian tumor progression by inhibiting myeloid-derived suppressor cell accumulation through KEAP1/Nrf2/ROS and NF-κB/PI3K/AKT/GSK3β cascades and by blocking lactotransferrin-induced MMP1 expression [PMID:34363021, PMID:32669559]."},"prefetch_data":{"uniprot":{"accession":"Q8WWA0","full_name":"Intelectin-1","aliases":["Endothelial lectin HL-1","Galactofuranose-binding lectin","Intestinal lactoferrin receptor","Omentin"],"length_aa":313,"mass_kda":35.0,"function":"Lectin that specifically recognizes microbial carbohydrate chains in a calcium-dependent manner (PubMed:11313366, PubMed:26148048). Binds to microbial glycans that contain a terminal acyclic 1,2-diol moiety, including beta-linked D-galactofuranose (beta-Galf), D-phosphoglycerol-modified glycans, D-glycero-D-talo-oct-2-ulosonic acid (KO) and 3-deoxy-D-manno-oct-2-ulosonic acid (KDO) (PubMed:26148048). Binds to glycans from Gram-positive and Gram-negative bacteria, including K.pneumoniae, S.pneumoniae, Y.pestis, P.mirabilis and P.vulgaris (PubMed:26148048). Does not bind human glycans (PubMed:26148048). Probably plays a role in the defense system against microorganisms (Probable). May function as adipokine that has no effect on basal glucose uptake but enhances insulin-stimulated glucose uptake in adipocytes (PubMed:16531507). Increases AKT phosphorylation in the absence and presence of insulin (PubMed:16531507). May interact with lactoferrin/LTF and increase its uptake, and may thereby play a role in iron absorption (PubMed:11747454, PubMed:23921499)","subcellular_location":"Cell membrane; Secreted","url":"https://www.uniprot.org/uniprotkb/Q8WWA0/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ITLN1","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/ITLN1","total_profiled":1310},"omim":[{"mim_id":"609874","title":"INTELECTIN 2; ITLN2","url":"https://www.omim.org/entry/609874"},{"mim_id":"609873","title":"INTELECTIN 1; ITLN1","url":"https://www.omim.org/entry/609873"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Vesicles","reliability":"Approved"},{"location":"Equatorial segment","reliability":"Approved"},{"location":"Acrosome","reliability":"Additional"},{"location":"Mid piece","reliability":"Additional"},{"location":"Principal piece","reliability":"Additional"}],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"adipose tissue","ntpm":714.6},{"tissue":"intestine","ntpm":1172.6}],"url":"https://www.proteinatlas.org/search/ITLN1"},"hgnc":{"alias_symbol":["ITLN","FLJ20022","LFR","HL-1","hIntL"],"prev_symbol":[]},"alphafold":{"accession":"Q8WWA0","domains":[{"cath_id":"3.90.215","chopping":"42-313","consensus_level":"medium","plddt":98.5657,"start":42,"end":313}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8WWA0","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8WWA0-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8WWA0-F1-predicted_aligned_error_v6.png","plddt_mean":92.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ITLN1","jax_strain_url":"https://www.jax.org/strain/search?query=ITLN1"},"sequence":{"accession":"Q8WWA0","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8WWA0.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8WWA0/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8WWA0"}},"corpus_meta":[{"pmid":"9501201","id":"PMC_9501201","title":"HL-1 cells: a cardiac muscle cell line that contracts and retains phenotypic characteristics of the adult cardiomyocyte.","date":"1998","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/9501201","citation_count":1305,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"14766671","id":"PMC_14766671","title":"Cardiac physiology at the cellular level: use of cultured HL-1 cardiomyocytes for studies of cardiac muscle cell structure and function.","date":"2004","source":"American journal of physiology. 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and response to metformin and lifestyle intervention in the diabetes prevention program.","date":"2010","source":"Diabetes","url":"https://pubmed.ncbi.nlm.nih.gov/20682687","citation_count":196,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"19913121","id":"PMC_19913121","title":"Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip.","date":"2009","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/19913121","citation_count":164,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"24768874","id":"PMC_24768874","title":"Omentin prevents myocardial ischemic injury through AMP-activated protein kinase- and Akt-dependent mechanisms.","date":"2014","source":"Journal of the American College of Cardiology","url":"https://pubmed.ncbi.nlm.nih.gov/24768874","citation_count":142,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"22081609","id":"PMC_22081609","title":"Fat-derived factor omentin stimulates endothelial cell function and ischemia-induced revascularization via endothelial nitric oxide synthase-dependent mechanism.","date":"2011","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/22081609","citation_count":140,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"26148048","id":"PMC_26148048","title":"Recognition of microbial glycans by human intelectin-1.","date":"2015","source":"Nature structural & molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/26148048","citation_count":132,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"22554771","id":"PMC_22554771","title":"Omentin plays an anti-inflammatory role through inhibition of TNF-α-induced superoxide production in vascular smooth muscle cells.","date":"2012","source":"European journal of pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/22554771","citation_count":130,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"23376485","id":"PMC_23376485","title":"Proteomic analysis of podocyte exosome-enriched fraction from normal human urine.","date":"2013","source":"Journal of proteomics","url":"https://pubmed.ncbi.nlm.nih.gov/23376485","citation_count":126,"is_preprint":false,"source_track":"gene2pubmed"}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":55547,"output_tokens":1163,"usd":0.092043},"stage2":{"model":"claude-opus-4-6","input_tokens":4381,"output_tokens":1538,"usd":0.090533},"total_usd":0.507893,"stage1_batch_id":"msgbatch_01DzrsgVgYngY1hvM3DU1yF2","stage2_batch_id":"msgbatch_01KA9b7iRzKFdhoBUT7vCvSe","note":"batch pricing = 50% of standard","round2_stage1":{"model":"claude-sonnet-4-6","input_tokens":69003,"output_tokens":5152,"usd":0.142145},"round2_rules_fired":"R3","round2_stage2":{"model":"claude-opus-4-6","input_tokens":8078,"output_tokens":3269,"usd":0.183172}},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2020,\n      \"finding\": \"ITLN1 suppresses lactotransferrin-driven ovarian cancer cell invasion by decreasing MMP1 expression, and induces a metabolic shift in metastatic ovarian cancer cells; treatment of ovarian cancer-bearing mice with ITLN1 markedly decreased tumor growth rates.\",\n      \"method\": \"In vitro functional assays (invasion, proliferation), MMP1 expression analysis, metabolic profiling, and in vivo mouse xenograft model with ITLN1 treatment\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean loss/gain-of-function with defined cellular and in vivo phenotypic readout, single lab\",\n      \"pmids\": [\"32669559\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ITLN1 inhibits tumor neovascularization and myeloid-derived suppressor cell (MDSC) accumulation in colorectal carcinoma by suppressing tumor-derived IL-17D and CXCL2 through the KEAP1/Nrf2/ROS/IL-17D and p65 NF-κB/CXCL2 signaling cascades, both dependent on PI3K/AKT/GSK3β; ITLN1 also inhibits bone marrow-derived hematopoietic progenitor cell differentiation into MDSCs and NOS2 activity on MDSCs.\",\n      \"method\": \"Orthotopic and subcutaneous tumor xenograft, bone marrow transplantation (H-2b+YFP+ chimerism), overexpression in CRC cells, PI3K inhibitor (LY294002), in vitro MDSC differentiation assays, NOS2 activity assays, T cell proliferation assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (in vivo xenograft, BM chimera, signaling pathway inhibition), single lab\",\n      \"pmids\": [\"34363021\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"The ITLN1 missense variant V109D does not influence ITLN1 glycan binding to β-D-galactofuranose or protein-protein oligomerization, indicating that CD-risk haplotype effects are unlikely to arise from altered carbohydrate recognition or oligomerization of ITLN1.\",\n      \"method\": \"Glycan-binding assay (β-D-galactofuranose), protein oligomerization assay, intestinal expression analysis by mRNA and protein quantification\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 — direct biochemical binding and oligomerization assays with defined variant, single lab\",\n      \"pmids\": [\"34145348\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Intelectin-1 (Itln1) is expressed in Paneth cells of mouse small intestine (in contrast to goblet-cell localization of human ITLN1); Itln1 knockout mice showed increased susceptibility in acute DSS-induced colitis, establishing a role for murine Itln1 in intestinal innate defense.\",\n      \"method\": \"Itln1 hypomorphic knockout mouse model, DSS colitis model (acute and chronic), mRNA and protein expression analysis, cell-type localization by immunohistochemistry\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO with defined in vivo phenotypic readout, single lab\",\n      \"pmids\": [\"36072603\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ITLN1 (intelectin-1/omentin) is a carbohydrate-binding protein expressed in intestinal epithelial cells (goblet cells in humans, Paneth cells in mice) that functions in innate immunity by binding microbial glycans; in cancer contexts, ITLN1 suppresses tumor progression by reducing MMP1-mediated invasion downstream of lactotransferrin signaling, inhibiting tumor neovascularization and MDSC accumulation via PI3K/AKT/GSK3β-dependent suppression of IL-17D and CXCL2; a common missense variant (V109D) does not alter its glycan-binding or oligomerization properties.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\nI'll systematically classify each paper, then extract discoveries only from KEEP papers.\n\n**Classification:**\n\nPapers 1-14, 16-32, 34-48, 50-51, 53, 55-82, 84-100 (from retrieved corpus): These are largely about HL-1 cardiomyocyte cell line, Arabidopsis LFR gene, or other topics unrelated to ITLN1. I need to identify which ones are actually about ITLN1.\n\n**KEEP from retrieved corpus:**\n- Paper [15]: ITLN1 modulates invasive potential in ovarian cancer — KEEP\n- Paper [49]: ITLN1 inhibits tumor neovascularization in colorectal carcinoma — KEEP\n- Paper [52]: Human intelectin-1 (ITLN1) genetic variation and intestinal expression — KEEP\n- Paper [82]: Characterization of Itln1 knockout mouse — KEEP\n- Paper [85]: ITLN in hybrid fish — borderline (fish ortholog, ITLN family); compatible with lectin function, KEEP as ortholog context\n- Paper [77]: GWAS variant of ITLN1 and type 2 diabetes — association study, EXCLUDE (no mechanism)\n- Paper [99]: rs2274907 allelic variant of ITLN1 gene in diabetic foot — association study, EXCLUDE\n- Paper [54], [83], [84], [95]: Arabidopsis LFR gene — SYMBOL COLLISION, EXCLUDE\n\n**KEEP from gene2pubmed corpus:**\n- Paper [16]: Human intelectin is a novel soluble lectin recognizing galactofuranose — KEEP (foundational mechanism)\n- Paper [17]: Genomic structure of human omentin (= intelectin/ITLN1) — KEEP\n- Paper [9]: Identification of omentin as novel adipokine (ITLN1/omentin) — KEEP (mechanism: enhances insulin-stimulated glucose uptake, Akt phosphorylation)\n- Paper [12]: Omentin plasma levels decreased in obesity — association, EXCLUDE\n- Paper [19]: Human intestinal lactoferrin receptor (= ITLN1) cloning — KEEP (mechanism)\n- Paper [15]: Mammalian lactoferrin receptors — KEEP (functional mechanism)\n- Paper [20]: Omentin inhibits TNF-induced vascular inflammation — KEEP (mechanism)\n- Paper [26]: Omentin prevents myocardial ischemic injury through AMPK/Akt — KEEP (mechanism)\n- Paper [27]: Omentin stimulates endothelial cell function via eNOS — KEEP (mechanism)\n- Paper [28]: Recognition of microbial glycans by human intelectin-1 — KEEP (structure + mechanism)\n- Paper [29]: Omentin anti-inflammatory role in SMCs — KEEP (mechanism)\n- Paper [21], [22]: Omentin serum levels/regulation — mostly association/expression, but [22] has ex vivo regulation by insulin/glucose — borderline KEEP for regulation mechanism\n- Papers [1-8], [10-11], [13-14], [23-25], [30]: GWAS/cDNA library/proteomics/GO tools — EXCLUDE (no ITLN1-specific mechanism)\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2001,\n      \"finding\": \"Human intelectin-1 (hIntL-1/ITLN1) was identified as a secretory glycoprotein that exists as a ~120 kDa homotrimer (three ~40 kDa subunits bridged by disulfide bonds) and binds D-galactofuranosyl residues and D-pentoses in a Ca2+-dependent manner, specifically recognizing bacterial arabinogalactan of Nocardia containing D-galactofuranosyl residues but not mammalian glycans.\",\n      \"method\": \"Recombinant protein expression, carbohydrate binding assays, native gel electrophoresis, Western blot under reducing/non-reducing conditions, RT-PCR for tissue expression\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstituted recombinant protein with direct binding assays and structural characterization, foundational paper\",\n      \"pmids\": [\"11313366\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"ITLN1 was cloned as a human intestinal lactoferrin receptor (LfR); the recombinant protein bound human lactoferrin with an apparent Kd of ~360 nM in a partially Ca2+-dependent manner, appeared as 136 kDa under non-reducing and 34 kDa under reducing conditions (consistent with a disulfide-linked homotetramer/multimer), was GPI-anchored on Caco-2 cells, and its overexpression in Caco-2 cells increased 125I-lactoferrin binding (1.7-fold) and 59Fe-lactoferrin uptake (3.4-fold), implicating it in iron uptake from lactoferrin.\",\n      \"method\": \"cDNA cloning, baculovirus expression/purification, 125I-lactoferrin binding assays, PI-PLC treatment, transfection into Caco-2 cells, 59Fe uptake assay\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstituted recombinant receptor, functional binding and iron uptake assays with gain-of-function validation\",\n      \"pmids\": [\"11747454\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Omentin (ITLN1) was identified as a novel visceral fat depot-specific secretory adipokine; recombinant omentin enhanced insulin-stimulated glucose uptake in human subcutaneous (~47%) and omental (~30%) adipocytes in vitro, and increased Akt phosphorylation both in the absence and presence of insulin, indicating it sensitizes adipocytes to insulin signaling through Akt activation.\",\n      \"method\": \"Recombinant protein treatment of primary human adipocytes, glucose uptake assay, Western blot for p-Akt, EST library sequencing, Northern blot for tissue distribution\",\n      \"journal\": \"American journal of physiology. Endocrinology and metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — recombinant protein with direct functional assay (glucose uptake) and molecular readout (Akt phosphorylation) in primary human cells\",\n      \"pmids\": [\"16531507\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"ITLN1/omentin gene structure was characterized, its promoter region defined, and sequence comparison revealed 100% identity between omentin and human intelectin-1, establishing these as the same protein. Omentin mRNA expression was found to differ in omental adipose tissue from patients with Crohn's disease, suggesting a role in intestinal barrier defense.\",\n      \"method\": \"Genomic sequencing, sequence alignment, RT-PCR of adipose tissue from IBD patients\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — sequence/expression analysis establishing protein identity, limited functional follow-up\",\n      \"pmids\": [\"16386808\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Omentin (ITLN1) inhibits TNF-α-induced vascular inflammation in human endothelial cells by activating AMPK (phospho-Thr172) and eNOS (phospho-Ser1177), increasing cGMP levels, and suppressing TNF-α-induced JNK phosphorylation and COX-2 expression; NOS inhibition reversed omentin's anti-inflammatory effect, placing eNOS/NO downstream of AMPK in the omentin signaling pathway.\",\n      \"method\": \"Recombinant omentin treatment of HUVECs, Western blot for phospho-AMPK/eNOS/JNK, enzyme immunoassay for cGMP, pharmacological inhibitors (NOS inhibitor, JNK inhibitor)\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — recombinant protein with multiple orthogonal readouts (AMPK, eNOS, cGMP, JNK, COX-2) and pathway dissection using inhibitors\",\n      \"pmids\": [\"21514279\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Omentin (ITLN1) promotes endothelial cell survival, differentiation into vascular tube-like structures, and ischemia-induced revascularization in vivo through an Akt→eNOS signaling pathway; AMPK acts upstream of Akt in this cascade, as dominant-negative AMPK reduced omentin-induced Akt phosphorylation; eNOS-knockout mice showed no revascularization response to omentin, confirming eNOS dependence in vivo.\",\n      \"method\": \"Adenoviral omentin overexpression in mice (limb ischemia model), HUVEC differentiation/survival assays with recombinant omentin, dominant-negative Akt/AMPK constructs, PI3K inhibitor (LY294002), NOS inhibitor, eNOS-knockout mice, Western blot for p-Akt/p-eNOS/p-AMPK\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal methods including genetic knockouts, dominant-negative constructs, pharmacological inhibitors, and in vivo model with mechanistic readouts\",\n      \"pmids\": [\"22081609\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Omentin (ITLN1) exerts anti-inflammatory effects in vascular smooth muscle cells by inhibiting TNF-α-induced superoxide production (NADPH oxidase activity), thereby preventing downstream activation of p38 and JNK kinases and suppression of VCAM-1 expression and monocyte adhesion; antioxidant N-acetyl-L-cysteine mimicked omentin's effect, confirming the ROS-dependent mechanism.\",\n      \"method\": \"Recombinant omentin treatment of SMCs, Western blot for p-p38/p-JNK/VCAM-1, lucigenin assay for NADPH oxidase activity, p38 and JNK inhibitors (SB203580, SP600125), N-acetyl-L-cysteine, monocyte adhesion assay, ex vivo rat aorta\",\n      \"journal\": \"European journal of pharmacology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — recombinant protein with multiple pathway inhibitors and orthogonal assays (biochemical + functional), replicated in ex vivo tissue\",\n      \"pmids\": [\"22554771\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Omentin (ITLN1) protects the myocardium from ischemia/reperfusion injury by suppressing cardiomyocyte apoptosis through both AMPK-dependent and Akt-dependent mechanisms; systemic omentin administration reduced infarct size in mice, and both fat-specific omentin overexpression and recombinant omentin in cultured cardiomyocytes (hypoxia/reoxygenation model) showed reduced apoptosis that was reversed by AMPK or Akt blockade.\",\n      \"method\": \"Mouse I/R model with systemic omentin injection, fat-specific omentin transgenic mice, cultured cardiomyocyte hypoxia/reoxygenation assay, AMPK and Akt inhibitors, Western blot for p-AMPK/p-Akt, apoptosis assays\",\n      \"journal\": \"Journal of the American College of Cardiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo model plus in vitro mechanistic dissection with genetic (transgenic) and pharmacological (kinase inhibitors) approaches\",\n      \"pmids\": [\"24768874\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Crystal structure of hIntL-1 (ITLN1) at 1.6 Å resolution complexed with β-D-galactofuranose (β-Galf) revealed that ITLN1 uses a bound calcium ion to coordinate terminal exocyclic 1,2-diol groups of microbial glycans; glycan microarray profiling showed ITLN1 binds exclusively microbial glycan epitopes (β-Galf, D-phosphoglycerol-modified glycans, heptoses, KO, KDO) and not any known human glycan epitopes; Neu5Ac (sialic acid), which also contains an exocyclic 1,2-diol, does not bind due to steric/electronic incompatibility; ITLN1 selectively marks Streptococcus pneumoniae serotypes bearing surface 1,2-diol glycans.\",\n      \"method\": \"X-ray crystallography (1.6 Å resolution), glycan microarray screening, recombinant protein, bacterial cell binding assays\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — high-resolution crystal structure with ligand, validated by glycan microarray and functional binding studies; independently strong evidence base\",\n      \"pmids\": [\"26148048\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ITLN1 suppresses ovarian cancer cell invasion and proliferation in the omental tumor microenvironment by: (1) inhibiting lactotransferrin-induced MMP1 expression to reduce invasive potential, and (2) inducing a metabolic shift in metastatic ovarian cancer cells; in vivo, ITLN1-treated tumor-bearing mice showed marked decreases in tumor growth rates.\",\n      \"method\": \"Ovarian cancer cell invasion/proliferation assays, MMP1 expression (Western blot/qRT-PCR), metabolic profiling, in vivo mouse xenograft model with ITLN1 treatment\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — multiple cellular assays plus in vivo model, but mechanistic pathway linking lactotransferrin→ITLN1→MMP1 relies partly on correlation\",\n      \"pmids\": [\"32669559\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ITLN1 suppresses colorectal carcinoma progression by inhibiting tumor vascularization and myeloid-derived suppressor cell (MDSC) accumulation; mechanistically, ITLN1 suppressed tumor-derived IL-17D via the KEAP1/Nrf2/ROS/IL-17D cascade and CXCL2 via p65 NF-κB/CXCL2 signaling, both dependent on PI3K/AKT/GSK3β; PI3K inhibitor LY294002 reversed these effects; ITLN1 also directly inhibited bone marrow HPC differentiation into MDSCs and NOS2 activity on MDSCs.\",\n      \"method\": \"Orthotopic and subcutaneous tumor xenografts, bone marrow transplantation (H-2b+YFP+ chimerism), ITLN1 overexpression in CRC cells, PI3K inhibitor, Western blot for KEAP1/Nrf2/NF-κB/AKT/GSK3β pathway components, MDSC functional assays (T cell suppression, NOS2, ROS), ELISA for IL-17D/CXCL2\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal in vivo models (orthotopic, subcutaneous, bone marrow chimera) plus pharmacological inhibition with defined molecular pathway readouts\",\n      \"pmids\": [\"34363021\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"The ITLN1 missense variant V109D does not alter glycan binding to β-D-galactofuranose or protein oligomerization, indicating this CD-risk-associated variant is functionally neutral for these core molecular activities; ITLN1 protein in the intestine is goblet-cell derived in humans.\",\n      \"method\": \"Glycan binding assays with recombinant V109D variant protein, oligomerization assays (native PAGE/SEC), immunohistochemistry/immunofluorescence of intestinal tissue\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct functional testing of variant protein for two specific activities (glycan binding, oligomerization) with appropriate controls\",\n      \"pmids\": [\"34145348\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In C57BL/6 mice, the functional ortholog Itln1 is expressed in Paneth cells (not goblet cells as in humans) of the small intestine; Itln1 knockout mice (hypomorphic allele, ~10,000-fold reduction) showed increased susceptibility to acute DSS-induced colitis but no significant effect on diet-induced obesity in two western-diet models, suggesting Itln1 plays a role in intestinal innate immunity but is not a major determinant of obesity/metabolic phenotype in this model.\",\n      \"method\": \"Itln1 knockout mouse generation (hypomorphic trapping allele), DSS colitis model (acute and chronic), diet-induced obesity model, Western blot and qRT-PCR for tissue expression, IHC for cell-type localization\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic knockout with defined in vivo phenotypic readouts in two disease models\",\n      \"pmids\": [\"36072603\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Insulin and glucose dose-dependently decreased omentin-1 (ITLN1) mRNA expression, protein levels, and secretion from omental adipose tissue explants ex vivo; hyperinsulinemic clamp in healthy subjects reduced plasma omentin-1 levels in vivo, establishing negative regulation of ITLN1 by insulin and glucose.\",\n      \"method\": \"Omental adipose tissue explant culture with insulin/glucose treatment, RT-PCR, Western blot, ELISA, hyperinsulinemic-euglycemic clamp in human subjects\",\n      \"journal\": \"Diabetes\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ex vivo tissue assays plus in vivo human physiological intervention, multiple readouts (mRNA, protein, secretion)\",\n      \"pmids\": [\"18174521\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ITLN1/omentin is a secreted, Ca2+-dependent homotrimeric lectin that recognizes exocyclic 1,2-diol groups on microbial-specific glycans (including β-galactofuranose, phosphoglycerol-modified glycans, and bacterial LPS components) but not human glycans, functioning in innate microbial surveillance; as an adipokine (omentin), it enhances insulin-stimulated Akt activation and glucose uptake in adipocytes, promotes endothelial survival and revascularization via AMPK→Akt→eNOS/NO signaling, exerts anti-inflammatory effects in vascular cells by suppressing TNF-α-induced ROS/JNK/p38/VCAM-1 and JNK/COX-2 pathways, protects the myocardium from ischemia/reperfusion injury through AMPK- and Akt-dependent anti-apoptotic mechanisms, and suppresses tumor progression in colorectal and ovarian cancer by inhibiting MMP1 expression, blocking IL-17D and CXCL2 production via KEAP1/Nrf2/ROS and NF-κB/PI3K/AKT/GSK3β cascades, and reducing myeloid-derived suppressor cell accumulation.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"ITLN1 (intelectin-1/omentin) is a secreted carbohydrate-binding lectin expressed in intestinal epithelial cells—goblet cells in humans and Paneth cells in mice—that functions in innate mucosal defense; Itln1-knockout mice exhibit increased susceptibility to DSS-induced colitis [PMID:36072603]. In cancer contexts, ITLN1 suppresses ovarian cancer cell invasion by decreasing lactotransferrin-driven MMP1 expression and reduces tumor growth in xenograft models [PMID:32669559]. ITLN1 also inhibits colorectal tumor neovascularization and myeloid-derived suppressor cell (MDSC) accumulation by suppressing IL-17D and CXCL2 through PI3K/AKT/GSK3β-dependent signaling cascades involving KEAP1/Nrf2/ROS and NF-κB pathways [PMID:34363021].\",\n  \"teleology\": [\n    {\n      \"year\": 2020,\n      \"claim\": \"Whether ITLN1 had direct anti-tumor effects was unknown; demonstration that ITLN1 suppresses lactotransferrin-driven MMP1 expression and ovarian cancer invasion, and reduces tumor growth in vivo, established ITLN1 as a tumor-suppressive secreted factor.\",\n      \"evidence\": \"In vitro invasion/proliferation assays, MMP1 expression analysis, metabolic profiling, and mouse xenograft model with recombinant ITLN1 treatment\",\n      \"pmids\": [\"32669559\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single lab; independent replication in additional tumor models needed\",\n        \"Direct receptor or signaling entry point for ITLN1 on cancer cells not identified\",\n        \"Metabolic reprogramming mechanism not molecularly defined\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"The signaling pathways through which ITLN1 remodels the tumor microenvironment were undefined; identification of PI3K/AKT/GSK3β-dependent suppression of IL-17D (via KEAP1/Nrf2/ROS) and CXCL2 (via NF-κB) established how ITLN1 inhibits tumor neovascularization and MDSC recruitment in colorectal carcinoma.\",\n      \"evidence\": \"Orthotopic/subcutaneous xenografts, bone marrow chimera with H-2b+YFP+ tracking, PI3K inhibitor (LY294002), in vitro MDSC differentiation and NOS2 activity assays\",\n      \"pmids\": [\"34363021\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single lab; pathway epistasis tested only with pharmacological PI3K inhibition, not genetic approaches\",\n        \"Direct molecular target/receptor mediating ITLN1 signaling on tumor cells unknown\",\n        \"Relevance to human CRC patients not validated\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Whether the Crohn's disease-associated V109D variant alters ITLN1 lectin function was unknown; biochemical assays showed no effect on β-D-galactofuranose binding or oligomerization, ruling out these mechanisms as the basis of disease-risk association.\",\n      \"evidence\": \"Glycan-binding assay (β-D-galactofuranose) and protein oligomerization assay with purified V109D variant\",\n      \"pmids\": [\"34145348\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Only one glycan ligand tested; broader glycan specificity effects not excluded\",\n        \"Mechanism by which the V109D haplotype confers disease risk remains unidentified\",\n        \"Expression-level or stability effects of V109D not fully resolved\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Whether ITLN1/Itln1 is required for intestinal innate defense in vivo was untested; Itln1-knockout mice showed increased susceptibility to acute DSS colitis, establishing a non-redundant protective role and revealing species-specific expression in Paneth cells rather than goblet cells.\",\n      \"evidence\": \"Itln1 hypomorphic knockout mouse, acute and chronic DSS colitis models, immunohistochemistry for cell-type localization\",\n      \"pmids\": [\"36072603\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Only hypomorphic allele used; complete null not characterized\",\n        \"Microbial targets bound by Itln1 in vivo not identified\",\n        \"Whether goblet-cell vs Paneth-cell expression reflects functional divergence between species is unknown\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The direct cell-surface receptor or binding partner through which ITLN1 transduces intracellular signals in both immune and cancer contexts remains unidentified, and the in vivo microbial glycan targets relevant to intestinal defense are not defined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No receptor for ITLN1 identified on epithelial, immune, or tumor cells\",\n        \"Full spectrum of microbial glycan ligands not mapped\",\n        \"Structural basis for ITLN1-mediated signaling unknown\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0, 1, 3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0168256\", \"supporting_discovery_ids\": [1, 3]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"MMP1\",\n      \"LTF\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"ITLN1 (intelectin-1/omentin) is a secreted, disulfide-linked homotrimeric lectin that functions in innate microbial surveillance and metabolic/vascular signaling. Its crystal structure reveals a Ca²⁺-coordinated binding site that selectively recognizes exocyclic 1,2-diol groups on microbial glycans—including β-D-galactofuranose, phosphoglycerol-modified glycans, heptoses, and KDO—while excluding all tested human glycan epitopes, enabling discrimination of microbial surfaces such as Streptococcus pneumoniae [PMID:26148048, PMID:11313366]. As a visceral-fat-derived adipokine, ITLN1 enhances insulin-stimulated Akt phosphorylation and glucose uptake in adipocytes [PMID:16531507], promotes endothelial survival and revascularization through an AMPK→Akt→eNOS/NO cascade [PMID:22081609], suppresses TNF-α-induced vascular inflammation by blocking NADPH oxidase-derived ROS and downstream JNK/p38/COX-2 signaling [PMID:21514279, PMID:22554771], and protects the myocardium from ischemia–reperfusion injury via AMPK- and Akt-dependent anti-apoptotic mechanisms [PMID:24768874]. ITLN1 also suppresses colorectal and ovarian tumor progression by inhibiting myeloid-derived suppressor cell accumulation through KEAP1/Nrf2/ROS and NF-κB/PI3K/AKT/GSK3β cascades and by blocking lactotransferrin-induced MMP1 expression [PMID:34363021, PMID:32669559].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Identification of ITLN1 as a Ca²⁺-dependent lectin that selectively recognizes microbial galactofuranose—and simultaneously as a GPI-anchored lactoferrin receptor mediating intestinal iron uptake—established its dual functional identity as both a pattern-recognition molecule and an intestinal receptor.\",\n      \"evidence\": \"Recombinant protein carbohydrate-binding assays and native gel electrophoresis (lectin function); baculovirus-expressed protein with ¹²⁵I-lactoferrin binding, PI-PLC release, and ⁵⁹Fe uptake in Caco-2 cells (lactoferrin receptor function)\",\n      \"pmids\": [\"11313366\", \"11747454\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis for glycan selectivity was unknown\",\n        \"Lactoferrin-receptor function has not been reconciled with lectin activity or confirmed in vivo\",\n        \"Native receptor on intestinal epithelium not characterized at the single-cell level\"\n      ]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Discovery that omentin (confirmed identical to intelectin-1) is a visceral-fat-derived adipokine that enhances insulin-stimulated glucose uptake via Akt activation reframed ITLN1 as a metabolic signaling molecule beyond its lectin role.\",\n      \"evidence\": \"Recombinant omentin treatment of primary human adipocytes with glucose uptake assay and p-Akt Western blot; sequence identity confirmation and tissue expression profiling\",\n      \"pmids\": [\"16531507\", \"16386808\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Cell-surface receptor mediating omentin's metabolic effects was not identified\",\n        \"Whether insulin-sensitizing activity occurs in vivo in humans was untested\",\n        \"Altered expression in Crohn's disease was correlative, not mechanistically dissected\"\n      ]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Demonstration that insulin and glucose negatively regulate ITLN1 expression and secretion from omental adipose tissue, including in vivo during hyperinsulinemic clamp, established a feedback loop linking metabolic state to ITLN1 levels.\",\n      \"evidence\": \"Omental adipose explant culture with insulin/glucose dose-response (RT-PCR, Western blot, ELISA) and hyperinsulinemic-euglycemic clamp in human subjects\",\n      \"pmids\": [\"18174521\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Transcription factors mediating insulin/glucose suppression were not defined\",\n        \"Physiological consequence of reduced ITLN1 in hyperinsulinemic states not established causally\"\n      ]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Pathway dissection in endothelial cells established that ITLN1 activates an AMPK→Akt→eNOS/NO signaling cascade that mediates both anti-inflammatory effects (suppressing TNF-α-induced JNK/COX-2) and pro-angiogenic effects (endothelial survival and revascularization in vivo), with eNOS-knockout mice confirming in vivo eNOS dependence.\",\n      \"evidence\": \"Recombinant omentin on HUVECs with pharmacological inhibitors and phospho-protein readouts; adenoviral omentin overexpression in mouse limb ischemia model; dominant-negative AMPK/Akt constructs; eNOS-knockout mice\",\n      \"pmids\": [\"21514279\", \"22081609\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Upstream receptor for ITLN1 on endothelial cells remains unidentified\",\n        \"Whether AMPK activation is direct or requires intermediate kinases was unknown\"\n      ]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Extension to vascular smooth muscle cells showed ITLN1 suppresses TNF-α-induced inflammation by inhibiting NADPH oxidase-derived superoxide, which prevents downstream p38/JNK activation and VCAM-1 expression, broadening its vascular anti-inflammatory mechanism beyond endothelium.\",\n      \"evidence\": \"Recombinant omentin on SMCs with lucigenin superoxide assay, pharmacological inhibitors (SB203580, SP600125, NAC), monocyte adhesion assay, and ex vivo rat aorta\",\n      \"pmids\": [\"22554771\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Direct molecular target of ITLN1 on SMCs not identified\",\n        \"In vivo relevance to atherosclerosis not tested genetically\"\n      ]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"ITLN1 was shown to protect the myocardium from ischemia–reperfusion injury by suppressing cardiomyocyte apoptosis through both AMPK-dependent and Akt-dependent mechanisms, extending its cytoprotective role to cardiac tissue.\",\n      \"evidence\": \"Mouse I/R model with systemic omentin injection, fat-specific omentin transgenic mice, cardiomyocyte hypoxia/reoxygenation assay, AMPK and Akt inhibitors\",\n      \"pmids\": [\"24768874\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether ITLN1 acts directly on cardiomyocytes or via paracrine intermediates was not resolved\",\n        \"No receptor identified on cardiomyocytes\"\n      ]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"The 1.6 Å crystal structure resolved how ITLN1 achieves microbial selectivity: a single Ca²⁺ ion coordinates terminal exocyclic 1,2-diol groups present on microbial but not human glycans, explaining why Neu5Ac (sialic acid) is excluded despite containing a 1,2-diol, and glycan microarray confirmed exclusive microbial-epitope binding.\",\n      \"evidence\": \"X-ray crystallography with β-Galf co-crystal, comprehensive glycan microarray, bacterial cell binding assays with S. pneumoniae serotypes\",\n      \"pmids\": [\"26148048\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No structure in complex with phosphoglycerol or heptose ligands\",\n        \"Downstream signaling triggered upon microbial glycan engagement is unknown\",\n        \"Whether ITLN1 opsonizes bacteria for phagocytosis or directly kills them was untested\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"ITLN1 was shown to suppress ovarian cancer invasion by inhibiting lactotransferrin-induced MMP1 expression and inducing a metabolic shift in metastatic cells, establishing an anti-tumor function in the omental microenvironment.\",\n      \"evidence\": \"Ovarian cancer invasion/proliferation assays, MMP1 Western blot/qRT-PCR, metabolic profiling, in vivo mouse xenograft model\",\n      \"pmids\": [\"32669559\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Causal link between lactotransferrin, ITLN1, and MMP1 relies partly on correlation\",\n        \"Metabolic shift mechanism not defined at the molecular level\",\n        \"Direct binding of ITLN1 to cancer cells vs. stromal-mediated effects not distinguished\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Mechanistic dissection of ITLN1's anti-tumor activity in colorectal cancer revealed suppression of MDSC recruitment through dual inhibition of IL-17D (via KEAP1/Nrf2/ROS) and CXCL2 (via NF-κB), both converging on PI3K/AKT/GSK3β; separately, the CD-associated V109D variant was shown to retain normal glycan binding and oligomerization, and mouse Itln1 knockout increased colitis susceptibility without affecting diet-induced obesity.\",\n      \"evidence\": \"Orthotopic/subcutaneous xenografts with bone marrow chimera, PI3K inhibitor, MDSC functional assays; recombinant V109D protein binding/oligomerization assays; Itln1 knockout mouse DSS colitis and western-diet models\",\n      \"pmids\": [\"34363021\", \"34145348\", \"36072603\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether V109D affects functions beyond glycan binding (e.g. adipokine signaling) is untested\",\n        \"Mouse knockout was hypomorphic (~10,000-fold reduction), not a true null\",\n        \"Receptor mediating ITLN1's PI3K/AKT activation on tumor cells is unknown\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The identity of the cell-surface receptor through which ITLN1 activates AMPK/Akt signaling on endothelial cells, cardiomyocytes, adipocytes, and tumor cells remains entirely unknown, representing the central unresolved question in ITLN1 biology.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No receptor has been identified for ITLN1 adipokine/signaling functions\",\n        \"Whether lectin (glycan-binding) and adipokine (signaling) functions use the same or distinct receptors is unknown\",\n        \"Effector mechanisms downstream of microbial glycan recognition (opsonization, complement, direct killing) are uncharacterized\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [0, 8]},\n      {\"term_id\": \"GO:0038024\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [2, 4, 5, 7, 10]},\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [2, 4, 5, 7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0, 2, 8, 13]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0168256\", \"supporting_discovery_ids\": [2, 4, 5, 7, 10]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [4, 5, 6, 7, 10]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [9, 10]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"LTF\",\n      \"PRKAA1\",\n      \"AKT1\",\n      \"NOS3\",\n      \"NFKB1\",\n      \"NFE2L2\",\n      \"MMP1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}