Affinage

IL36A

Interleukin-36 alpha · UniProt Q9UHA7

Round 2 corrected
Length
158 aa
Mass
17.7 kDa
Annotated
2026-04-28
127 papers in source corpus 14 papers cited in narrative 14 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

IL-36α is a pro-inflammatory IL-1 family cytokine that functions as an agonist of the IL-1Rrp2/IL-1RAcP heterodimeric receptor complex to activate NF-κB, AP-1, and MAPK (p38, JNK, ERK1/2) signaling via a MyD88/TRAF6/IRAK1/TAK1 signaling module, driving production of chemokines (CXCL1, CXCL2, IL-8), IL-6, and antimicrobial peptides in keratinocytes, intestinal epithelial cells, synovial fibroblasts, and myeloid cells (PMID:14734551, PMID:26752465, PMID:24829417). Full agonist activity requires N-terminal proteolytic removal of a prodomain—achievable by neutrophil elastase—which increases specific activity by 10³–10⁴-fold (PMID:21965679, PMID:29142248). IL-36α activity is antagonized by IL-36Ra (IL-1F5), which binds IL-1Rrp2 and prevents IL-1RAcP co-recruitment; genetic deletion of IL-36Ra in mice expressing an IL-36α transgene exacerbates skin inflammation (PMID:11466363, PMID:17908936). IL-36 receptor signaling promotes mucosal inflammation in colitis models and shapes T helper polarization during enteric infection, and IL-36α is markedly upregulated in psoriatic skin and inflamed colonic mucosa (PMID:26813344, PMID:21242515).

Mechanistic history

Synthesis pass · year-by-year structured walk · 8 steps
  1. 2000 Medium

    Identification of IL-36α as a novel IL-1 family member (FIL1ε/IL-1H1) with a predicted β-barrel fold and gene localization to the IL-1 cluster on chromosome 2q established its molecular identity, while initial expression profiling revealed constitutive expression in squamous epithelium and inducibility by IFN-γ and TNF-α in keratinocytes.

    Evidence cDNA cloning, structural modeling, Northern blot, keratinocyte stimulation, and in vivo contact-hypersensitivity/HSV models

    PMID:10625660 PMID:10744718

    Open questions at the time
    • No receptor identified at this stage
    • No functional activity assay performed
    • Protein processing requirements unknown
  2. 2001 High

    The first functional assay demonstrated that IL-36α activates NF-κB through the orphan receptor IL-1Rrp2 and that IL-36Ra (IL-1F5) specifically blocks this activation, establishing an agonist–antagonist signaling axis distinct from classical IL-1.

    Evidence NF-κB luciferase reporter assays with IL-1Rrp2 transfection and IL-1F5 antagonism

    PMID:11466363

    Open questions at the time
    • Role of co-receptor (IL-1RAcP) not yet established
    • Downstream signaling cascades beyond NF-κB unknown
  3. 2004 High

    IL-1RAcP was identified as an essential co-receptor: dominant-negative IL-1RAcP and neutralizing anti-IL-1Rrp2 antibodies blocked IL-36α signaling, and JNK/ERK1/2 MAPK cascades were identified as additional downstream effectors alongside NF-κB, with IL-6 and IL-8 as functional outputs.

    Evidence Receptor transfection, dominant-negative IL-1RAcP, neutralizing antibodies, MAPK Western blotting, IL-6/IL-8 secretion assays in multiple cell lines

    PMID:14734551

    Open questions at the time
    • Structural basis for IL-1Rrp2/IL-1RAcP heterodimerization not resolved
    • Requirement for N-terminal processing not yet recognized
  4. 2007 High

    In vivo genetic evidence confirmed the agonist–antagonist paradigm: transgenic IL-36α expression in mouse basal keratinocytes caused IL-1Rrp2/IL-1RAcP-dependent skin inflammation, and concurrent IL-36Ra knockout exacerbated the phenotype, proving IL-36Ra is a physiological antagonist in vivo.

    Evidence Transgenic/knockout mouse crosses with histopathology and cytokine expression analysis

    PMID:17908936

    Open questions at the time
    • Endogenous protease responsible for IL-36α activation in skin not identified
    • Relative contribution of IL-36α vs. other IL-36 agonists in skin inflammation unclear
  5. 2011 High

    Two key advances clarified IL-36α biology: systematic N-terminal truncation showed that prodomain removal increases specific activity by 10³–10⁴-fold, explaining previously discrepant dose–response data; and IL-36α was found massively upregulated in psoriatic skin where it induces antimicrobial peptides (HBD-2, HBD-3, CAMP) in reconstituted human epidermis.

    Evidence Recombinant truncation series with quantitative NF-κB reporter dose–response; qRT-PCR on patient biopsies; reconstituted human epidermis stimulation

    PMID:21242515 PMID:21965679

    Open questions at the time
    • In vivo protease responsible for N-terminal processing not yet identified
    • Role in psoriasis causation vs. consequence not formally tested
  6. 2014 High

    Cellular target breadth was expanded beyond epithelia: monocytes, myeloid DCs, and monocyte-derived DCs were shown to express IL-36R and respond to IL-36α by producing IL-1β and IL-6 and upregulating maturation markers; IL-36α-treated DCs enhanced CD4+ T cell proliferation, establishing a link between IL-36α and adaptive immune priming.

    Evidence In vivo intradermal injection, flow cytometry, ELISA, in vitro monocyte/DC stimulation, allogeneic T cell proliferation assays

    PMID:24829417

    Open questions at the time
    • Whether IL-36α acts directly on T cells not resolved
    • Relative potency of IL-36α vs. IL-36β/γ on myeloid cells not compared
  7. 2016 High

    Two studies established IL-36α function in the intestinal compartment: IL-36R-deficient mice showed reduced DSS colitis severity and altered T helper polarization (enhanced Th17, reduced Th1) during Citrobacter rodentium infection; mechanistically, IL-36α assembles a MyD88/TRAF6/IRAK1/TAK1 complex in intestinal epithelial cells to activate NF-κB, AP-1, and MAPKs for CXC chemokine production.

    Evidence IL-36R knockout mice in DSS colitis and enteric infection models; co-immunoprecipitation of signaling complex, siRNA and pharmacological pathway inhibition in HT-29 cells

    PMID:26752465 PMID:26813344

    Open questions at the time
    • Specific IL-36α protease in the intestinal milieu not identified
    • Whether IL-36α signals in intestinal immune cells independently of epithelial chemokine induction not established
  8. 2017 Medium

    Neutrophil elastase was identified as a physiologically relevant protease that cleaves the IL-36 prodomain to generate active cytokine, and truncated IL-36 cytokines were shown to synergize with IL-17A in regulating keratinocyte differentiation, connecting neutrophil recruitment to amplification of IL-36 signaling.

    Evidence 3D organotypic skin models, incubation with purified neutrophil elastase, N-terminal sequencing, gene expression analysis

    PMID:29142248

    Open questions at the time
    • Whether elastase is the predominant processing protease in vivo or if other proteases contribute
    • Structural basis of IL-36/IL-17A synergistic signaling not resolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structural basis of the IL-36α/IL-1Rrp2/IL-1RAcP ternary complex, the full repertoire of activating proteases across tissues, direct effects on lymphocyte subsets, and whether IL-36α has non-redundant functions relative to IL-36β and IL-36γ.
  • No crystal structure of IL-36α/receptor complex
  • Non-redundancy among IL-36 agonists not tested by individual genetic deletion
  • Intracellular vs. extracellular processing compartment undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 5
Localization
GO:0005576 extracellular region 3
Pathway
R-HSA-168256 Immune System 6 R-HSA-162582 Signal Transduction 3
Partners
IL1RAPIL1RL2IL36RNIRAK1MAP3K7MYD88TRAF6

Evidence

Reading pass · 14 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 IL-1F6 (later renamed IL-36α) activates NF-κB signaling through the orphan receptor IL-1Rrp2 (IL-1R-related protein 2), while the closely related IL-1F5 (IL-36Ra) specifically and potently inhibits this IL-1F6/IL-36α response, establishing an independent agonist/antagonist signaling system at IL-1Rrp2. NF-κB–luciferase reporter assays in transfected cell lines; IL-1F5 antagonism of IL-1F6-induced NF-κB activation Journal of immunology (Baltimore, Md. : 1950) High 11466363
2000 IL-36α (designated FIL1ε) was cloned as a novel IL-1 family member; protein structure modeling predicts a beta-barrel fold shared with IL-1β/IL-1Ra, and the gene maps to the IL-1 cluster on human chromosome 2q. EST database searches, cDNA cloning, protein structure modeling, chromosomal mapping The Journal of biological chemistry Medium 10625660
2000 IL-36α (designated IL-1H1) is constitutively expressed in placenta and squamous epithelium of the esophagus, and can be induced in keratinocytes by IFN-γ and TNF-α in vitro and by contact hypersensitivity or herpes simplex virus infection in vivo, suggesting a role in immune-mediated epithelial responses. Northern blot, in vitro keratinocyte stimulation, in vivo contact hypersensitivity and HSV infection models The Journal of biological chemistry Medium 10744718
2004 IL-36α (IL-1F6), IL-36β (IL-1F8), and IL-36γ (IL-1F9) all signal through both IL-1Rrp2 and IL-1RAcP to activate the NF-κB pathway and MAPKs (JNK and ERK1/2), and downstream targets including an IL-8 promoter and IL-6 secretion. Antibodies to IL-1Rrp2 block signaling, and cytoplasmically-deleted IL-1RAcP acts as a dominant negative, establishing IL-1RAcP as an essential co-receptor. NF-κB reporter assays, receptor transfection, neutralizing antibodies to IL-1Rrp2, dominant-negative IL-1RAcP transfection, MAPK Western blotting, IL-6/IL-8 secretion assays in multiple cell lines The Journal of biological chemistry High 14734551
2007 Transgenic expression of IL-1F6 (IL-36α) in basal keratinocytes in mice caused skin inflammation (acanthosis, hyperkeratosis, mixed inflammatory infiltrate, elevated cytokines/chemokines) in an IL-1Rrp2– and IL-1RAcP–dependent manner. Genetic deletion of IL-1F5 (IL-36Ra) in these mice exacerbated the phenotype, providing in vivo genetic evidence that IL-1F5 is a functional antagonist of IL-1F6/IL-36α. Transgenic mouse generation, genetic epistasis (IL-1F6 transgene × IL-1F5 knockout), histopathology, cytokine/chemokine expression analysis The Journal of experimental medicine High 17908936
2011 Full agonist activity of IL-36α (IL-1F6) requires N-terminal truncation to remove a prodomain; truncated IL-36α has ~10³–10⁴-fold greater specific activity (EC₅₀ shifting from ~1 μg/ml to ~1 ng/ml), demonstrating that post-translational proteolytic processing is required for full IL-36α activity. N-terminal truncation series of recombinant proteins, NF-κB reporter assays comparing full-length vs. truncated forms The Journal of biological chemistry High 21965679
2011 IL-36α (IL-1F6) and related IL-1F cytokines are markedly upregulated in psoriatic skin (2–3 orders of magnitude vs. uninvolved skin), and are induced in normal keratinocytes by IL-1α and TNF-α. IL-36α and IL-1F8 induce expression of antimicrobial peptides (HBD-2, HBD-3, CAMP) and matrix metalloproteinases in reconstituted human epidermis. Quantitative RT-PCR, immunohistochemistry, in vitro keratinocyte stimulation, reconstituted human epidermis model, microarray analysis Journal of immunology (Baltimore, Md. : 1950) Medium 21242515
2012 IL-36α is expressed by CD138+ plasma cells in psoriatic arthritis and rheumatoid arthritis synovium. Recombinant IL-36α activates synovial fibroblasts (FLS) to produce IL-6 and IL-8 through p38 MAPK and NF-κB signaling pathways. Immunohistochemistry, immunofluorescence, Western blot, quantitative RT-PCR, multiplex cytokine assay, immunoblotting for p38/NF-κB activation in FLS Annals of the rheumatic diseases Medium 23268368
2014 Intradermal injection of IL-36α in mice induces chemokine expression (CXCL1, CXCL8, CCL3, CCL5, CCL20), leukocyte infiltration, and acanthosis. Blood monocytes, myeloid dendritic cells, and monocyte-derived DCs express IL-36R and respond directly to IL-36α by upregulating IL-1β and IL-6 production and DC maturation markers (CD83, CD86, HLA-DR); IL-36α–treated monocyte-derived DCs enhance allogeneic CD4+ T cell proliferation. In vivo intradermal injection, flow cytometry, ELISA, RT-PCR; in vitro monocyte/DC stimulation assays Journal of immunology (Baltimore, Md. : 1950) High 24829417
2016 IL-36α expression is specifically elevated in colonic mucosa of ulcerative colitis patients and in DSS colitis mice. IL-36R-deficient mice exhibit reduced disease severity in DSS colitis with decreased innate inflammatory cell infiltration, and show increased bacterial colonization and altered T helper (enhanced Th17, reduced Th1) responses upon Citrobacter rodentium infection, establishing IL-36R/IL-36α signaling as a mediator of colonic mucosal inflammation and host defense. RT-PCR on patient biopsies, DSS colitis mouse model, Citrobacter rodentium infection model, flow cytometry, IL-36R knockout mice Mucosal immunology High 26813344
2016 IL-36α induces expression of CXC chemokines (CXCL1, CXCL2, CXCL3) in intestinal epithelial cells by assembling a MyD88/TRAF6/IRAK1/TAK1 signaling complex that activates NF-κB, AP-1, and MAPK phosphorylation; NF-κB and c-Jun AP-1 siRNA knockdown and MAPK inhibitors reduce IL-36α–induced chemokine expression. ELISA, Western blot, co-immunoprecipitation of signaling complex, siRNA knockdown of NF-κB/AP-1, MAPK inhibitors, RT-PCR in HT-29 cells Inflammatory bowel diseases High 26752465
2017 IL-36γ (and by implication other IL-36 agonists including IL-36α) is secreted from keratinocytes in an inactive form and is proteolytically activated by neutrophil-derived proteases, including neutrophil elastase, which cleaves the N-terminal prodomain to generate the active truncated form. Truncated IL-36 cytokines cooperate synergistically with IL-17A to regulate keratinocyte differentiation and target gene expression. 3D organotypic skin models, recombinant protein incubation with purified proteases, N-terminal sequencing, gene expression analysis Scientific reports Medium 29142248
2006 IL-36α (IL-1 family member 6 / IL-1F6) was identified as a nitroprotein in human pituitary adenoma tissue by nitrotyrosine affinity chromatography and tandem mass spectrometry, demonstrating that IL-36α undergoes tyrosine nitration as a post-translational modification in vivo. Nitrotyrosine affinity column enrichment, trypsin digestion, tandem mass spectrometry Analytical biochemistry Low 16777052
2015 High-throughput affinity-purification mass spectrometry (BioPlex) identified interaction partners for IL-36α (IL-1F6) in HEK293T cells, placing it within the human interactome network. Affinity-purification mass spectrometry (AP-MS), BioPlex network Cell Low 26186194

Source papers

Stage 0 corpus · 127 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2015 The BioPlex Network: A Systematic Exploration of the Human Interactome. Cell 1118 26186194
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
1987 Human recombinant interleukin 4 induces Fc epsilon receptors (CD23) on normal human B lymphocytes. The Journal of experimental medicine 556 2953844
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2004 Interleukin (IL)-1F6, IL-1F8, and IL-1F9 signal through IL-1Rrp2 and IL-1RAcP to activate the pathway leading to NF-kappaB and MAPKs. The Journal of biological chemistry 346 14734551
1988 Human recombinant interleukin 4 induces Fc epsilon R2/CD23 on normal human monocytes. The Journal of experimental medicine 313 2965737
2007 Opposing activities of two novel members of the IL-1 ligand family regulate skin inflammation. The Journal of experimental medicine 288 17908936
2011 Interleukin-36 (IL-36) ligands require processing for full agonist (IL-36α, IL-36β, and IL-36γ) or antagonist (IL-36Ra) activity. The Journal of biological chemistry 285 21965679
1986 Fc epsilon receptor, a specific differentiation marker transiently expressed on mature B cells before isotype switching. The Journal of experimental medicine 283 2945890
1994 A physical map of the region encompassing the human interleukin-1 alpha, interleukin-1 beta, and interleukin-1 receptor antagonist genes. Genomics 281 8188271
2000 Four new members expand the interleukin-1 superfamily. The Journal of biological chemistry 276 10625660
2000 Identification and initial characterization of four novel members of the interleukin-1 family. The Journal of biological chemistry 275 10744718
2008 Signalling adaptors used by Toll-like receptors: an update. Cytokine 265 18706831
2011 IL-1F5, -F6, -F8, and -F9: a novel IL-1 family signaling system that is active in psoriasis and promotes keratinocyte antimicrobial peptide expression. Journal of immunology (Baltimore, Md. : 1950) 254 21242515
2014 IL-36 promotes myeloid cell infiltration, activation, and inflammatory activity in skin. Journal of immunology (Baltimore, Md. : 1950) 253 24829417
2009 The cytokine interleukin-33 mediates anaphylactic shock. Proceedings of the National Academy of Sciences of the United States of America 227 19506243
2001 Two novel IL-1 family members, IL-1 delta and IL-1 epsilon, function as an antagonist and agonist of NF-kappa B activation through the orphan IL-1 receptor-related protein 2. Journal of immunology (Baltimore, Md. : 1950) 213 11466363
2002 Lipopolysaccharide regulates proinflammatory cytokine expression in mouse myoblasts and skeletal muscle. American journal of physiology. Regulatory, integrative and comparative physiology 196 12185005
2003 IL-1 induces vesicular secretion of IL-6 without degranulation from human mast cells. Journal of immunology (Baltimore, Md. : 1950) 183 14568962
2000 A phosphatidylinositol 3-kinase/Akt pathway, activated by tumor necrosis factor or interleukin-1, inhibits apoptosis but does not activate NFkappaB in human endothelial cells. The Journal of biological chemistry 181 10748004
2000 Association of an interleukin 1 alpha polymorphism with Alzheimer's disease. Neurology 173 10953177
2001 IL-1H, an interleukin 1-related protein that binds IL-18 receptor/IL-1Rrp. Cytokine 169 11145836
2001 Cloning and characterization of IL-1HY2, a novel interleukin-1 family member. The Journal of biological chemistry 169 11278614
2002 A sequence-based map of the nine genes of the human interleukin-1 cluster. Genomics 168 11991722
2006 The omega-3 fatty acid docosahexaenoate attenuates endothelial cyclooxygenase-2 induction through both NADP(H) oxidase and PKC epsilon inhibition. Proceedings of the National Academy of Sciences of the United States of America 165 17018645
2009 Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip. American journal of human genetics 164 19913121
2002 Protein kinase C-zeta regulates transcription of the matrix metalloproteinase-9 gene induced by IL-1 and TNF-alpha in glioma cells via NF-kappa B. The Journal of biological chemistry 162 12130632
2019 An update on generalized pustular psoriasis. Expert review of clinical immunology 152 31486687
2000 Molecular cloning and expression analysis of carp (Cyprinus carpio) interleukin-1 beta, high affinity immunoglobulin E Fc receptor gamma subunit and serum amyloid A. Fish & shellfish immunology 146 10938736
2012 The novel cytokine interleukin-36α is expressed in psoriatic and rheumatoid arthritis synovium. Annals of the rheumatic diseases 142 23268368
2000 Identification and gene organization of three novel members of the IL-1 family on human chromosome 2. Genomics 140 10860666
1989 Regulation of human basophil mediator release by cytokines. I. Interaction with antiinflammatory steroids. Journal of immunology (Baltimore, Md. : 1950) 138 2473127
1993 The 31-kDa precursor of interleukin 1 alpha is myristoylated on specific lysines within the 16-kDa N-terminal propiece. Proceedings of the National Academy of Sciences of the United States of America 127 8346241
2001 A new nomenclature for IL-1-family genes. Trends in immunology 121 11574262
2016 IL-36α expression is elevated in ulcerative colitis and promotes colonic inflammation. Mucosal immunology 118 26813344
1992 Modulation of IL-4 induced germline epsilon RNA synthesis in human B cells by tumor necrosis factor-alpha, anti-CD40 monoclonal antibodies or transforming growth factor-beta correlates with levels of IgE production. International immunology 118 1373645
2019 Biology of IL-36 Signaling and Its Role in Systemic Inflammatory Diseases. Frontiers in immunology 114 31736959
2016 Increased Expression of Interleukin-36, a Member of the Interleukin-1 Cytokine Family, in Inflammatory Bowel Disease. Inflammatory bowel diseases 113 26752465
1990 Cytokine receptors and B cell functions. I. Recombinant soluble receptors specifically inhibit IL-1- and IL-4-induced B cell activities in vitro. Journal of immunology (Baltimore, Md. : 1950) 113 2139075
2017 The psoriasis-associated IL-17A induces and cooperates with IL-36 cytokines to control keratinocyte differentiation and function. Scientific reports 104 29142248
1988 Production of B cell-stimulating factors by B cells in patients with systemic lupus erythematosus. Journal of immunology (Baltimore, Md. : 1950) 102 3262675
1992 Myristyl acylation of the tumor necrosis factor alpha precursor on specific lysine residues. The Journal of experimental medicine 101 1402651
1991 FK-506, a potent novel inhibitor of the release of proinflammatory mediators from human Fc epsilon RI+ cells. Journal of immunology (Baltimore, Md. : 1950) 101 1706398
2006 Nitroproteins from a human pituitary adenoma tissue discovered with a nitrotyrosine affinity column and tandem mass spectrometry. Analytical biochemistry 100 16777052
1994 An endogenous lectin, galectin-3 (epsilon BP/Mac-2), potentiates IL-1 production by human monocytes. Immunology letters 100 7890309
2015 Interleukin-36α axis is modulated in patients with primary Sjögren's syndrome. Clinical and experimental immunology 86 25902739
2009 Sustained viral gene delivery through core-shell fibers. Journal of controlled release : official journal of the Controlled Release Society 85 19539680
1989 Influence of recombinant IL-4, IFN-alpha, and IFN-gamma on the production of human IgE-binding factor (soluble CD23). Journal of immunology (Baltimore, Md. : 1950) 80 2521231
1999 IL1HY1: A novel interleukin-1 receptor antagonist gene. Biochemical and biophysical research communications 76 10512743
2016 Anatomically shaped tissue-engineered cartilage with tunable and inducible anticytokine delivery for biological joint resurfacing. Proceedings of the National Academy of Sciences of the United States of America 75 27432980
1992 Effects of cyclosporin A and FK506 on Fc epsilon receptor type I-initiated increases in cytokine mRNA in mouse bone marrow-derived progenitor mast cells: resistance to FK506 is associated with a deficiency in FK506-binding protein FKBP12. Proceedings of the National Academy of Sciences of the United States of America 72 1382293
2008 Crucial role of phospholipase C epsilon in skin inflammation induced by tumor-promoting phorbol ester. Cancer research 70 18172297
2010 New genetic associations detected in a host response study to hepatitis B vaccine. Genes and immunity 69 20237496
1997 Cytokine mRNA expression in human platelets and a megakaryocytic cell line and cytokine modulation of platelet function. Cytokine 67 9199874
2017 IL-1/inhibitory κB kinase ε-induced glycolysis augment epithelial effector function and promote allergic airways disease. The Journal of allergy and clinical immunology 66 29108965
1994 Intrinsic human glomerular mesangial cells can express receptors for IgG complexes (hFc gamma RIII-A) and the associated Fc epsilon RI gamma-chain. Journal of immunology (Baltimore, Md. : 1950) 64 8027555
1999 Mechanism of IL-1 induced inhibition of protein synthesis in skeletal muscle. Shock (Augusta, Ga.) 58 10220298
1990 IL-3 promotes production of IL-4 by splenic non-B, non-T cells in response to Fc receptor cross-linkage. Journal of immunology (Baltimore, Md. : 1950) 53 2145362
1996 Cross-linking of T-cell receptors on double-positive thymocytes induces a cytokine-mediated stromal activation process linked to cell death. The EMBO journal 52 8918465
1991 In vivo modulation of the distribution of thymocyte subsets: effects of estrogen on the expression of different T cell receptor V beta gene families in CD4-, CD8- thymocytes. Cellular immunology 52 1708703
2014 Interleukin-1β reduces L-type Ca2+ current through protein kinase Cϵ activation in mouse heart. The Journal of biological chemistry 51 24936064
2018 Novel nano therapeutic materials for the effective treatment of rheumatoid arthritis-recent insights. Materials today. Communications 49 32289062
2019 3D-Printed Bioactive Calcium Silicate/Poly-ε-Caprolactone Bioscaffolds Modified with Biomimetic Extracellular Matrices for Bone Regeneration. International journal of molecular sciences 48 30795573
2005 Regulation of c-Jun phosphorylation by the I kappa B kinase-epsilon complex in fibroblast-like synoviocytes. Journal of immunology (Baltimore, Md. : 1950) 46 15879144
1999 AND-34, a novel p130Cas-binding thymic stromal cell protein regulated by adhesion and inflammatory cytokines. Journal of immunology (Baltimore, Md. : 1950) 45 10438950
1994 Distinct patterns of differentiation induced in the monocytic cell line Mono Mac 6. Journal of leukocyte biology 44 8283142
1998 Regulation of cyclooxygenase-2 and endogenous cytokine expression by bacterial lipopolysaccharide that acts in synergy with c-kit ligand and Fc epsilon receptor I crosslinking in cultured mast cells. Cellular immunology 42 9636692
1997 Bacterial lipopolysaccharide induces early and late activation of protein kinase C in inflammatory macrophages by selective activation of PKC-epsilon. Biochemical and biophysical research communications 42 9398616
1995 Interleukin 4 suppresses c-kit ligand-induced expression of cytosolic phospholipase A2 and prostaglandin endoperoxide synthase 2 and their roles in separate pathways of eicosanoid synthesis in mouse bone marrow-derived mast cells. Proceedings of the National Academy of Sciences of the United States of America 39 7541141
1994 Possible role of protein kinase C-epsilon isoenzyme in inhibition of interleukin 1 beta induction of nitric oxide synthase in rat renal mesangial cells. The Biochemical journal 37 7526844
1990 IFN-alpha and IFN-gamma have different regulatory effects on IL-4-induced membrane expression of Fc epsilon RIIb and release of soluble Fc epsilon RIIb by human monocytes. Journal of immunology (Baltimore, Md. : 1950) 36 2139077
2000 Loss of Ikappa B-beta is associated with prolonged NF-kappa B activity in human glial cells. The Journal of biological chemistry 35 10998424
2004 A polymorphism of the interleukin-1 beta gene at position +3953 influences progression and neuro-pathological hallmarks of Alzheimer's disease. Neurobiology of aging 34 15212826
1992 Retinoic acid and phorbol ester synergistically up-regulate IL-8 expression and specifically modulate protein kinase C-epsilon in human skin fibroblasts. Journal of immunology (Baltimore, Md. : 1950) 33 1323613
1991 Down-regulation by interleukin 4 of activation of human alveolar macrophages to the tumoricidal state. Cancer research 31 1913671
2001 Expression and regulation of inducible IkappaB kinase (IKK-i) in human fibroblast-like synoviocytes. Cellular immunology 30 11902829
1996 Regulation of peptide-chain initiation in muscle during sepsis by interleukin-1 receptor antagonist. The American journal of physiology 28 8843745
1993 Differential expression of CR3, Fc epsilon RII and Fc gamma RIII on polymorphonuclear leukocytes in gingival crevicular fluid. Journal of periodontal research 28 8410601
2020 Intra-articular delivery of flurbiprofen sustained release thermogel: improved therapeutic outcome of collagenase II-induced rat knee osteoarthritis. Drug delivery 26 32627602
2018 IL4-10 fusion protein: a novel immunoregulatory drug combining activities of interleukin 4 and interleukin 10. Clinical and experimental immunology 26 30307604
2008 Interleukin-1 beta (C-511T) genetic polymorphism is associated with cognitive performance in elderly males without dementia. Neurobiology of aging 26 19013689
1989 Differential regulation of the low affinity Fc receptor for IgE (Fc epsilon R2/CD23) and the IL-2 receptor (Tac/p55) on eosinophilic leukemia cell line (EoL-1 and EoL-3). Journal of immunology (Baltimore, Md. : 1950) 26 2525145
1997 B cell receptor cross-linking prevents Fas-induced cell death by inactivating the IL-1 beta-converting enzyme protease and regulating Bcl-2/Bcl-x expression. Journal of immunology (Baltimore, Md. : 1950) 25 9317114
1996 PDGF and IL-1 induce and activate specific protein kinase C isoforms in mesangial cells. The American journal of physiology 23 8760250
2002 Transient platelet interaction induces MCP-1 production by endothelial cells via I kappa B kinase complex activation. Thrombosis and haemostasis 22 12195705
1990 Interleukin 4 and interferons alpha and gamma regulate Fc epsilon R2/CD23 mRNA expression on normal human B cells. Molecular immunology 22 2138708
1989 Mast cells: immunologically specific effectors and potential sources of multiple cytokines during IgE-dependent responses. Ciba Foundation symposium 22 2515950
1996 Differential effects of protein kinase C inhibitors on chemokine production in human synovial fibroblasts. British journal of pharmacology 21 8882622
1992 Anti-inflammatory effects of nedocromil sodium: inhibition of alveolar macrophage function. Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology 21 1334783
2019 Tissue-type plasminogen activator neutralizes LPS but not protease-activated receptor-mediated inflammatory responses to plasmin. Journal of leukocyte biology 20 30690783
2003 Joint analysis of candidate genes related to Alzheimer's disease in a Spanish population. Psychiatric genetics 20 12782964
1996 An age-related decrease in rescue from T cell death following costimulation mediated by CD28. Cellular immunology 20 8660810
1993 Antigen presenting cell-derived co-stimulatory signals can selectively regulate IL-2 and IL-4 production from a Th0 cell hybridoma. International immunology 20 8494819
2003 Thermal injury impairs cardiac protein synthesis and is associated with alterations in translation initiation. American journal of physiology. Regulatory, integrative and comparative physiology 19 14695116
1994 Effect of a lipopeptidic formulation on macrophage activation and peptide presentation to T cells. Vaccine 19 7839726
1993 Quantitative analysis of polymerase chain reaction products using biotinylated dUTP incorporation. Analytical biochemistry 18 8103647
2020 Calcitonin inhibits intervertebral disc degeneration by regulating protein kinase C. Journal of cellular and molecular medicine 17 32564456
2020 Scoparone alleviates hepatic fibrosis by inhibiting the TLR-4/NF-κB pathway. Journal of cellular physiology 16 33090488
1997 Nuclear lipid-dependent signal transduction in human osteosarcoma cells. Advances in enzyme regulation 16 9381981
2022 Poly ε-Caprolactone Nanoparticles for Sustained Intra-Articular Immune Modulation in Adjuvant-Induced Arthritis Rodent Model. Pharmaceutics 15 35335895
1989 Interleukins in immunologic and allergic diseases. Annals of allergy 14 2679243
1997 Staurosporine, but not Ro 31-8220, induces interleukin 2 production and synergizes with interleukin 1alpha in EL4 thymoma cells. The Biochemical journal 13 9224627
1992 Induction and function of Fc epsilon RII on YT cells; possible role of ADF/thioredoxin in Fc epsilon RII expression. Immunobiology 13 1452201
1997 Interleukin-1beta-induced expression of protein kinase C (PKC)-delta and epsilon in NIH 3T3 cells. Cytokine 11 9245485
1994 Granulocyte-macrophage colony-stimulating factor stimulates macrophages to respond to IgE via the low affinity IgE receptor (CD23). The Journal of allergy and clinical immunology 11 8151065
1992 Stimulation of a T helper cell class 2 clone with immobilized anti-T cell receptor antibody activates a Ca2+ and protein kinase C-independent lethal signaling pathway. Journal of immunology (Baltimore, Md. : 1950) 11 1533650
2019 A systems pharmacology workflow with experimental validation to assess the potential of anakinra for treatment of focal and segmental glomerulosclerosis. PloS one 10 30921378
1993 The effect of interferon-gamma, interleukin-4 and immunoglobulin receptor cross-linking of monocytes on allergen-specific T-cell response. Immunology 10 8509138
1989 Multiple effects of human recombinant interleukin 4 on human myeloid monocyte cell lines. Immunology letters 10 2475440
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