Affinage

IRF6

Interferon regulatory factor 6 · UniProt O14896

Length
467 aa
Mass
53.1 kDa
Annotated
2026-06-10
100 papers in source corpus 22 papers cited in narrative 22 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

IRF6 is a transcription factor that occupies a central node in epithelial differentiation and craniofacial morphogenesis, where it governs the keratinocyte proliferation-to-differentiation switch and the loss-of-function mutations cause the Mendelian orofacial clefting disorders Van der Woude syndrome and popliteal pterygium syndrome (PMID:12219090). IRF6 sits within a regulatory circuit in which it is transcriptionally activated by p63 through the MCS9.7 enhancer and reciprocally drives proteasomal down-regulation of p63, a feedback loop that limits keratinocyte proliferative potential and restrains invasive behavior (PMID:21807998, PMID:24442519); it is also a primary Notch target gene whose induction promotes terminal differentiation and opposes ras-driven tumorigenesis (PMID:21909072). Full transcriptional activation requires priming by the kinase RIPK4, which phosphorylates IRF6 at Ser413 and Ser424; through this axis IRF6 occupies bivalent promoters and directs a terminal-differentiation program including lipid metabolism and tight junction genes necessary for the epidermal barrier (PMID:31578523). During palatal fusion IRF6 acts downstream of TGFβ/SMAD4 signalling to drive p21 expression and medial edge epithelium degeneration (PMID:23406900), operates in convergent pathways with the Notch ligand Jagged2 and the stratifin Sfn to maintain the oral periderm (PMID:17041603, PMID:19439425), and participates in genetic networks with Twist1, Esrp1/2, Tfap2a–Grhl3, and SPECC1L that pattern craniofacial and neural tube development (PMID:30689861, PMID:28769044, PMID:33234718, PMID:31943082). Beyond development, IRF6 functions as a specificity-determining mediator of innate immune signalling in keratinocytes, driving IL-36γ, CCL5/CXCL11, and IL-23p19 expression downstream of TLR2/TLR3 and RIPK4 (PMID:26303210, PMID:26819203, PMID:27014863), and it suppresses PPARγ to constrain M2 macrophage polarization (PMID:28645193). In cancer, epigenetic silencing of IRF6 by the EMT factors ZEB1 and SNAIL confers resistance to TNF-α-mediated apoptosis and T-cell killing (PMID:38378697).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 2002 High

    Establishing that IRF6 mutations cause human orofacial clefting syndromes defined IRF6 as an essential regulator of epithelial and craniofacial development, anchoring all subsequent mechanistic work.

    Evidence Mutation screening of Van der Woude/popliteal pterygium syndrome families plus in situ expression of Irf6 mRNA

    PMID:12219090

    Open questions at the time
    • Molecular target genes of IRF6 not yet defined
    • Upstream regulators of IRF6 expression unknown
  2. 2006 High

    Mouse genetics showed that IRF6 controls the keratinocyte proliferation-to-differentiation switch, explaining the epithelial fusions seen in disease.

    Evidence Homozygous missense knock-in mouse and Irf6;Sfn compound heterozygote epistasis with hyperproliferation/differentiation-failure phenotype

    PMID:17041603

    Open questions at the time
    • Molecular mechanism by which IRF6 enforces differentiation not resolved
    • How Sfn and IRF6 intersect biochemically unknown
  3. 2009 High

    IRF6 was placed in a convergent pathway with the Notch ligand Jagged2 controlling oral periderm formation, linking it to palatal adhesion and fusion.

    Evidence Mouse genetic analysis of Irf6 and Jagged2 mutants with histological characterization of periderm

    PMID:19439425

    Open questions at the time
    • Direct biochemical link between IRF6 and Notch signalling not established here
    • Periderm-specific IRF6 targets unidentified
  4. 2011 High

    Defining the p63→IRF6→p63 feedback loop and genome-wide IRF6 targets converted IRF6 from a genetic locus into a characterized transcription factor restraining proliferation and invasion.

    Evidence ChIP-seq, siRNA knockdown, gene expression profiling, invasion assays and IRF6 re-expression in SCC cells; plus Notch gain/loss-of-function and in vivo tumour assays

    PMID:21807998 PMID:21909072

    Open questions at the time
    • Mechanism of IRF6-driven p63 proteasomal degradation not detailed
    • Post-translational control of IRF6 activity not yet known
  5. 2013 High

    Genetic and rescue experiments established TGFβ/SMAD4 as an upstream activator of IRF6 driving p21 expression and medial edge epithelium degeneration during palatal fusion.

    Evidence Mouse conditional knockouts, compound heterozygotes, and Irf6 overexpression rescue of Tgfbr2-deficient MEE persistence with p21 immunostaining

    PMID:23406900

    Open questions at the time
    • Direct transcriptional regulation of Irf6 by SMAD4 not demonstrated
    • Whether p21 is a direct IRF6 target unresolved
  6. 2013 Medium

    Lineage tracing revealed both cell-autonomous (muscle/cytoskeletal) and non-cell-autonomous roles for IRF6 in tongue development, broadening its developmental scope beyond epithelium.

    Evidence Fate mapping, Irf6 knockout analysis, and molecular readout of Bmp/Shh/Fgf signalling in tongue

    PMID:23451037

    Open questions at the time
    • Mechanism of non-cell-autonomous signalling effects unknown
    • Single lab, correlative pathway readouts
  7. 2014 High

    Dissection of the MCS9.7 enhancer showed how a regulatory mutation reprograms IRF6 expression through dual loss and gain of transcription-factor binding, explaining noncoding clefting risk.

    Evidence Enhancer reporter assays, transgenic mouse lacZ assay, site-directed mutagenesis, and binding assays for p63/E47/Lef1

    PMID:24442519

    Open questions at the time
    • In vivo contribution of Lef1/β-Catenin repression not quantified
    • Other enhancers controlling IRF6 not mapped
  8. 2015 Medium

    Functional studies positioned IRF6 as a downstream effector of TGFβ3-driven EMT during palatal fusion, acting through SNAI2.

    Evidence Palatal organ culture rescue, shRNA knockdown, ectopic IRF6 expression, and EMT marker analysis

    PMID:26240017

    Open questions at the time
    • Whether SNAI2 is a direct IRF6 target not shown
    • Reconciliation with IRF6's anti-EMT role in tumors unresolved
  9. 2015 Medium

    IRF6 was identified as a specificity-determining switch in TLR3 signalling, biasing keratinocytes toward IL-23p19 and away from IFN-β.

    Evidence siRNA silencing, promoter reporter assays, co-IP and proximity ligation in primary keratinocytes

    PMID:26303210

    Open questions at the time
    • IRF6 binding partner mediating promoter selectivity not defined
    • In vivo relevance to skin immunity not tested
  10. 2016 Medium

    Two studies extended IRF6 into innate immune cytokine induction, defining IRAK1→IRF6 (IL-36γ) and RIPK4→IRF6 (CCL5/CXCL11) axes in epithelial inflammation.

    Evidence siRNA silencing and promoter reporter assays with TLR2/PKC stimulation and RIPK4 overexpression in oral keratinocytes

    PMID:26819203 PMID:27014863

    Open questions at the time
    • Direct IRF6 binding to cytokine promoters not all confirmed by ChIP
    • Single lab reporter-based evidence
  11. 2017 Medium

    Identification of NME1/NME2 as direct IRF6 interactors revealed a cytoplasmic, phosphorylation-dependent function linking IRF6 to Rho GTPase regulation, beyond its nuclear transcriptional role.

    Evidence Yeast two-hybrid, co-IP, phosphorylation and Rac1/RhoA activation assays, and co-localization in primary palatal epithelial cells

    PMID:28767310

    Open questions at the time
    • Functional consequence of cytoplasmic IRF6 in vivo unclear
    • How nuclear vs cytoplasmic IRF6 pools are partitioned unknown
  12. 2017 Medium

    Epistasis with Twist1 demonstrated an epithelial-to-mesenchymal intercellular signalling role for IRF6 acting through EDN1/DLX/HAND2 in craniofacial skeletal development.

    Evidence Mouse single/double heterozygotes, gene expression analysis, and EDN1 rescue of mandibular explants

    PMID:28769044

    Open questions at the time
    • Secreted mediator transmitting the epithelial-mesenchymal signal not identified
    • Direct vs indirect regulation of EDN1 unknown
  13. 2017 Medium

    IRF6 was shown to directly repress PPARγ transcription, constraining M2 macrophage polarization and extending IRF6 function to immune cell programming.

    Evidence Gain/loss-of-function and ChIP confirming IRF6 occupancy at the PPARγ locus

    PMID:28645193

    Open questions at the time
    • Physiological context of macrophage IRF6 expression unclear
    • Single lab
  14. 2019 High

    Identification of RIPK4 as the kinase phosphorylating IRF6 at Ser413/Ser424 provided the priming mechanism for IRF6 activation and tied IRF6 directly to bivalent-promoter control of the epidermal barrier program.

    Evidence Kinase-dead knock-in mouse, phosphosite mapping, RNA-seq/ChIP-seq/ATAC-seq, and stratum corneum lipid/barrier assays

    PMID:31578523

    Open questions at the time
    • Structural basis of phospho-priming not resolved
    • How phosphorylation alters IRF6 DNA binding/coactivator recruitment unknown
  15. 2019 Medium

    Gain- and loss-of-function established a Tfap2a–Irf6–Grhl3 genetic pathway operating in neurulation, generalizing IRF6's morphogenetic role to neural tube closure.

    Evidence Transgenic Irf6 overexpression and loss-of-function mice with Tfap2a/Grhl3 expression analysis

    PMID:30689861

    Open questions at the time
    • Direct transcriptional regulation among pathway members not demonstrated
    • Single lab
  16. 2020 Medium

    Cross-species genetics defined an Irf6–Esrp1/2 axis and placed SPECC1L downstream of IRF6 in midface and periderm morphogenesis, refining the developmental network.

    Evidence Zebrafish knockouts with neural crest lineage tracing, mouse compound mutants, and Irf6-mutant SPECC1L immunostaining

    PMID:31943082 PMID:33234718

    Open questions at the time
    • Direct vs indirect regulation of esrp1/SPECC1L by IRF6 not established
    • Single method for the IRF6-SPECC1L link
  17. 2020 Medium

    IRF6 was shown to repress glycolytic genes PKM2 and GLUT1 in glioma and to be controlled post-transcriptionally by a Lin28A/SNHG14/STAU1 axis, extending IRF6 to tumor metabolism.

    Evidence ChIP, knockdown/overexpression, and xenograft assays

    PMID:32527996

    Open questions at the time
    • Relevance of glioma metabolic role to epithelial IRF6 biology unclear
    • Single lab
  18. 2024 Medium

    IRF6 was identified as a downstream mediator of EMT-driven immune evasion, with ZEB1/SNAIL silencing of IRF6 conferring resistance to TNF-α apoptosis and T-cell killing.

    Evidence Mouse PDAC relapse model, EMT-TF manipulation, epigenetic analysis, and TNF-α killing assays

    PMID:38378697

    Open questions at the time
    • IRF6 target genes mediating TNF-α sensitivity not defined
    • Whether human tumors recapitulate this silencing not shown

Open questions

Synthesis pass · forward-looking unresolved questions
  • The structural and biochemical basis by which phosphorylation, cytoplasmic interactors, and chromatin context switch IRF6 between activator and repressor functions across epithelial, immune, and tumor contexts remains unresolved.
  • No structural model of activated IRF6 on target promoters
  • Determinants of context-specific target selection unknown
  • Mechanism integrating nuclear transcription and cytoplasmic Rho GTPase roles unclear

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 4 GO:0003677 DNA binding 3
Localization
GO:0005634 nucleus 2 GO:0005829 cytosol 1
Pathway
R-HSA-1266738 Developmental Biology 5 R-HSA-168256 Immune System 4 R-HSA-1640170 Cell Cycle 3 R-HSA-74160 Gene expression (Transcription) 3
Partners
NME1NME2RIPK4SFNSMAD4TP63

Evidence

Reading pass · 22 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2002 Loss-of-function (nonsense/missense) mutations in IRF6 cause Van der Woude syndrome and popliteal pterygium syndrome. IRF6 mRNA is highly expressed along the medial edge of the fusing palate, tooth buds, hair follicles, genitalia and skin, establishing a direct role for IRF6 in orofacial and epithelial development. Mutation screening of VWS/PPS families; in situ expression analysis of Irf6 mRNA Nature genetics High 12219090
2006 Mice homozygous for a missense mutation in Irf6 develop a hyperproliferative epidermis that fails to undergo terminal differentiation, resulting in soft tissue fusions. Compound heterozygosity for Irf6 and Sfn (14-3-3σ/stratifin) recapitulates similar keratinizing epithelial defects, placing Irf6 and Sfn in a shared genetic pathway controlling the keratinocyte proliferation-differentiation switch. Mouse genetics (homozygous missense knock-in); compound heterozygote epistasis analysis Nature genetics High 17041603
2009 IRF6 is essential for oral epithelial differentiation and functions in a convergent molecular pathway with the Notch ligand Jagged2. IRF6 plays a key role in formation and maintenance of the oral periderm, with spatio-temporal regulation of this periderm being essential for appropriate palatal adhesion and fusion. Mouse genetic analysis (Irf6 mutant and Jagged2 mutant); histological and molecular characterization of palatal/oral epithelium Human molecular genetics High 19439425
2011 IRF6 is transcriptionally activated by p63 and, in turn, induces proteasome-mediated down-regulation of p63, forming a regulatory feedback loop that limits keratinocyte proliferative potential. ChIP-seq and gene expression profiling after siRNA-mediated IRF6 depletion revealed direct IRF6 target genes involved in cell cycle, differentiation, cell adhesion, and cell–cell contact. IRF6 down-regulation promotes invasive behavior in squamous cell carcinoma cells. ChIP-seq for IRF6 binding sites; siRNA knockdown; gene expression profiling; in vitro invasion assays; re-expression of IRF6 in SCC cells Proceedings of the National Academy of Sciences of the United States of America High 21807998
2011 IRF6 is induced during keratinocyte differentiation through a Notch-dependent mechanism and is a primary Notch target gene in keratinocytes and keratinocyte-derived SCC cells. Increased IRF6 expression contributes to Notch-driven regulation of growth/differentiation genes, while it is not required for induction of canonical Notch targets (p21WAF1/Cip1, Hes1, Hey1). Down-modulation of IRF6 counteracts differentiation and promotes ras-induced tumour formation. Notch gain-of-function; IRF6 siRNA knockdown; gene expression analysis; in vivo tumour formation assay The EMBO journal High 21909072
2013 TGFβ signaling regulates expression of Irf6, and IRF6 and SMAD4 synergistically regulate the fate of the medial edge epithelium (MEE) during palatal fusion. Haploinsufficiency of Irf6 in Smad4 conditional knockout mice causes compromised p21 expression and MEE persistence. Overexpression of Irf6 rescued p21 expression and MEE degeneration in Tgfbr2-deficient mice, establishing TGFβ-mediated Irf6 activity as responsible for MEE degeneration. Mouse genetics (conditional knockout, compound heterozygotes); Irf6 overexpression rescue experiment; p21 immunostaining Development (Cambridge, England) High 23406900
2019 RIPK4 kinase activity is required for mouse development; RIPK4 phosphorylates IRF6 at Ser413 and Ser424, priming IRF6 for activation. RNA-seq, ChIP-seq, and ATAC-seq of wild-type versus IRF6-deficient skin showed IRF6 is enriched at bivalent promoters and its deficiency causes defective expression of genes involved in lipid metabolism and tight junction formation, culminating in a severe epidermal barrier defect. Kinase-dead knock-in mouse; phosphosite mapping (Ser413/Ser424); RNA-seq; ChIP-seq; ATAC-seq; lipid composition analysis of stratum corneum Nature High 31578523
2015 TLR3 stimulation of keratinocytes upregulates IRF6, which selectively promotes IL-23p19 expression while suppressing IFN-β expression. IRF6 silencing enhanced poly(IC)-inducible IFN-β mRNA and inhibited IL-23p19 mRNA. Co-transfection of IRF6 increased IL-23p19 promoter activity but inhibited IFN-β promoter activity, defining IRF6 as a specificity-determining downstream mediator of TLR3 signalling. siRNA silencing of IRF6; gene reporter (promoter) assays; co-immunoprecipitation; proximity ligation assay Immunology and cell biology Medium 26303210
2016 IRF6 acts downstream of IRAK1 to stimulate expression of the pro-inflammatory cytokine IL-36γ in oral epithelial cells in response to Porphyromonas gingivalis (via TLR2). Gene silencing and promoter reporter experiments confirmed IRF6 drives IL-36γ transcription. Gene silencing (siRNA); promoter reporter assays; TLR2 agonist stimulation Journal of immunology (Baltimore, Md. : 1950) Medium 26819203
2016 RIPK4 overexpression in oral keratinocytes induces CCL5 and CXCL11 expression in an IRF6-dependent manner. Gene silencing of RIPK4 or IRF6 abolished PKC pathway-induced CCL5/CXCL11 expression. Promoter reporter assays showed RIPK4 stimulates transactivation of CCL5 and CXCL11 promoters by IRF6, establishing a RIPK4→IRF6 signalling axis for proinflammatory cytokine induction in keratinocytes. RIPK4 overexpression; siRNA knockdown of RIPK4 and IRF6; gene reporter (promoter) assays; PKC pathway activation Cytokine Medium 27014863
2015 IRF6 is a mediator of TGFβ3 during palatal fusion: ectopic IRF6 expression rescued shTgfβ3-induced fusion defects in palatal organ culture. IRF6 increases SNAI2 (Slug) expression and decreases epithelial markers (E-cadherin, Plakophilin, ZO-1), regulating epithelial–mesenchymal transition (EMT) during palatal fusion. Knockdown of Snai2 abolished the IRF6 rescuing effect. Palatal shelf organ culture; shRNA knockdown; ectopic IRF6 expression; RT-PCR and protein analysis of EMT markers Scientific reports Medium 26240017
2017 IRF6 suppresses PPARγ transcription by binding IRF recognition sites upstream of the PPARγ coding region, thereby suppressing alternative (M2) macrophage polarization. ChIP confirmed IRF6 occupancy at the PPARγ locus. IRF6 knockdown enhanced M2 activation; IRF6 overexpression dramatically attenuated it. Gain- and loss-of-function (overexpression and siRNA); chromatin immunoprecipitation (ChIP); computational binding site prediction Endocrinology Medium 28645193
2014 A regulatory mutation (350dupA) in the IRF6 enhancer element MCS9.7 abrogates binding of p63 and E47 transcription factors to overlapping cis-motifs, significantly disrupting enhancer activity. The 350dupA simultaneously creates a CAAAGT motif bound by Lef1; Lef1/β-Catenin chimeric protein repressed MCS9.7-350dupA enhancer activity, demonstrating a dual loss-of-function/gain-of-function mechanism regulating IRF6 expression. Enhancer reporter assays in human cell cultures; transgenic mouse lacZ reporter assay; site-directed mutagenesis of binding motifs; Lef1 overexpression; electrophoretic mobility shift / binding assays Human molecular genetics High 24442519
2017 IRF6 is identified as a direct protein interactor of NME1 and NME2 (regulators of Rho-type GTPases and E-cadherin endocytosis) by yeast two-hybrid screening and co-immunoprecipitation. The IRF6–NME interaction is enhanced by phosphorylation of key serine residues in the IRF6 C-terminus. CLP-associated IRF6 missense mutations disrupt NME binding and result in elevated Rac1 and RhoA activation. NME1 and NME2 co-localize with IRF6 in the cytoplasm of primary palatal epithelial cells in vivo. Yeast two-hybrid screen; co-immunoprecipitation; phosphorylation assays; Rac1/RhoA activation assays; co-localization in primary palatal epithelial cells Journal of dental research Medium 28767310
2019 Overexpression of Irf6 in mice causes exencephaly through suppression of Tfap2a and Grhl3 expression, while loss of Irf6 function causes curly tail with reduced Tfap2a and Grhl3 expression in tail tissues, demonstrating that a Tfap2a–Irf6–Grhl3 genetic pathway operates during neurulation as well as orofacial development. Transgenic Irf6 overexpression mouse model; Irf6 loss-of-function mouse; gene expression analysis of Tfap2a and Grhl3 Human molecular genetics Medium 30689861
2017 Loss of Irf6 in mice causes craniosynostosis and mandibular hypoplasia. Double heterozygous Irf6+/−;Twist1+/− embryos show severe mandibular hypoplasia with reduced EDN1, DLX5, DLX6 and HAND2 expression in mesenchymal cells, demonstrating an intercellular genetic interaction between Irf6 (expressed in epithelium) and Twist1 (expressed in mesenchyme). Exogenous EDN1 peptide partially rescued Meckel's cartilage abnormalities. Mouse genetics (single and double heterozygotes); gene expression analysis; mandibular explant culture with EDN1 rescue Scientific reports Medium 28769044
2013 Irf6 is expressed in Myf5+ (segmental paraxial mesoderm) cells of the developing tongue. Loss of Irf6 causes reduced and poorly organized Myf5+ cell lineage and aberrant cytoskeletal formation. Non-cell-autonomously, loss of Irf6 alters Bmp2, Bmp4, Shh, and Fgf10 signalling in the tongue, establishing both cell-autonomous (muscle differentiation/cytoskeletal organization) and non-cell-autonomous (cranial neural crest-derived inter-molar eminence) roles for IRF6. Lineage tracing (fate mapping); dual-label immunostaining; Irf6 knockout mouse analysis; molecular analysis of signalling pathway genes PloS one Medium 23451037
2020 In zebrafish, irf6 regulates the expression of esrp1. Genetic disruption of irf6 and esrp1/2 in zebrafish results in cleft of the anterior neurocranium due to impaired chondrogenesis (not a neural crest migration defect). Mouse compound mutant analysis showed genetic interaction between Irf6 and Esrp1, with Irf6 heterozygosity reducing Esrp1/2 cleft severity, defining an Irf6–Esrp1/2 regulatory axis in midface morphogenesis. Zebrafish genetic knockouts; cranial neural crest lineage tracing; mouse compound mutant breeding; gene expression analysis Development (Cambridge, England) Medium 33234718
2020 SPECC1L expression is drastically reduced in Irf6 mutant palatal shelves, placing SPECC1L downstream of IRF6 in palatogenesis. Specc1l mutant mice display periderm layer abnormalities and transient oral epithelial adhesions similar to Irf6 hypomorphic mutants. Irf6 mutant mouse analysis; immunostaining for SPECC1L expression; phenotypic comparison of mutant palatal shelves Human molecular genetics Medium 31943082
2024 In a mouse PDAC model, acquired resistance to immunotherapy is associated with EMT. EMT-transcription factors ZEB1 and SNAIL epigenetically and transcriptionally silence IRF6, rendering tumor cells resistant to the pro-apoptotic effects of TNF-α and insensitive to T-cell killing. This identifies IRF6 as a downstream mediator of EMT-driven immune evasion. Mouse PDAC tumor relapse model; EMT transcription factor manipulation; epigenetic analysis; TNF-α killing assays Nature communications Medium 38378697
2008 IRF6 interacts with maspin (a known tumor suppressor) in mammary epithelial cells and functions to regulate cell cycle exit and entry into G0 quiescence, promoting mammary epithelial cell differentiation. Protein interaction (co-immunoprecipitation implied by 'interaction with maspin'); cell cycle analysis in mammary epithelial cells Cell cycle (Georgetown, Tex.) Low 18604160
2020 IRF6 inhibits transcription of PKM2 and GLUT1 in glioma cells, thereby impairing glycolysis. SNHG14 lncRNA sequesters STAU1 to prevent IRF6 mRNA degradation via its 3' UTR, increasing IRF6 expression; Lin28A stabilizes SNHG14. Depleting Lin28A or SNHG14 or overexpressing IRF6 reduced xenograft tumor growth. siRNA/shRNA knockdown; overexpression; ChIP (IRF6 binding to PKM2/GLUT1 promoters); xenograft mouse model; RT-PCR and western blot Cell death & disease Medium 32527996

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1990 CD14, a receptor for complexes of lipopolysaccharide (LPS) and LPS binding protein. Science (New York, N.Y.) 3460 1698311
2002 Mutations in IRF6 cause Van der Woude and popliteal pterygium syndromes. Nature genetics 657 12219090
1994 Lipopolysaccharide (LPS)-binding protein accelerates the binding of LPS to CD14. The Journal of experimental medicine 622 7505800
2019 Innate immunity to intracellular LPS. Nature immunology 489 30962589
1999 Relationship between plasma levels of lipopolysaccharide (LPS) and LPS-binding protein in patients with severe sepsis and septic shock. The Journal of infectious diseases 484 10515819
2019 Pushing the envelope: LPS modifications and their consequences. Nature reviews. Microbiology 391 31142822
2016 Reconstruction of LPS Transfer Cascade Reveals Structural Determinants within LBP, CD14, and TLR4-MD2 for Efficient LPS Recognition and Transfer. Immunity 345 27986454
1998 LPS-binding proteins and receptors. Journal of leukocyte biology 341 9665271
2009 Evolution of lipopolysaccharide (LPS) recognition and signaling: fish TLR4 does not recognize LPS and negatively regulates NF-kappaB activation. Journal of immunology (Baltimore, Md. : 1950) 306 19201835
1989 Lipopolysaccharide (LPS) binding protein opsonizes LPS-bearing particles for recognition by a novel receptor on macrophages. The Journal of experimental medicine 295 2477488
2006 Irf6 is a key determinant of the keratinocyte proliferation-differentiation switch. Nature genetics 278 17041603
1998 LPS-binding protein protects mice from septic shock caused by LPS or gram-negative bacteria. The Journal of clinical investigation 270 9593762
1997 T cell stimulation in vivo by lipopolysaccharide (LPS). The Journal of experimental medicine 262 9182680
2001 Intestinal macrophages lack CD14 and CD89 and consequently are down-regulated for LPS- and IgA-mediated activities. Journal of immunology (Baltimore, Md. : 1950) 245 11509607
2007 Structural biology of the LPS recognition. International journal of medical microbiology : IJMM 216 17481951
2016 Both systemic and local lipopolysaccharide (LPS) burden are associated with knee OA severity and inflammation. Osteoarthritis and cartilage 207 27216281
1992 Control of lipopolysaccharide (LPS) binding and LPS-induced tumor necrosis factor secretion in human peripheral blood monocytes. Journal of immunology (Baltimore, Md. : 1950) 207 1375247
2020 Neuroprotection by dihydrotestosterone in LPS-induced neuroinflammation. Neurobiology of disease 193 32087283
2019 ACE2 exhibits protective effects against LPS-induced acute lung injury in mice by inhibiting the LPS-TLR4 pathway. Experimental and molecular pathology 175 31805278
2001 Plasma CD14 decreases monocyte responses to LPS by transferring cell-bound LPS to plasma lipoproteins. The Journal of clinical investigation 161 11489942
2003 Lipopolysaccharide (LPS)-binding protein mediates LPS detoxification by chylomicrons. Journal of immunology (Baltimore, Md. : 1950) 154 12538700
2006 LPS-induced TNF-alpha factor (LITAF)-deficient mice express reduced LPS-induced cytokine: Evidence for LITAF-dependent LPS signaling pathways. Proceedings of the National Academy of Sciences of the United States of America 153 16954198
2011 Developmental factor IRF6 exhibits tumor suppressor activity in squamous cell carcinomas. Proceedings of the National Academy of Sciences of the United States of America 142 21807998
2017 Corylin protects LPS-induced sepsis and attenuates LPS-induced inflammatory response. Scientific reports 129 28397806
2009 Integration of IRF6 and Jagged2 signalling is essential for controlling palatal adhesion and fusion competence. Human molecular genetics 116 19439425
1999 A growing family of receptor genes for lysophosphatidic acid (LPA) and other lysophospholipids (LPs). Cell biochemistry and biophysics 116 10356643
1995 Enzymatically deacylated lipopolysaccharide (LPS) can antagonize LPS at multiple sites in the LPS recognition pathway. The Journal of biological chemistry 114 7537270
2018 Serum amyloid A promotes LPS clearance and suppresses LPS-induced inflammation and tissue injury. EMBO reports 111 30126923
2016 Micheliolide inhibits LPS-induced inflammatory response and protects mice from LPS challenge. Scientific reports 106 26984741
2011 IRF6 is a mediator of Notch pro-differentiation and tumour suppressive function in keratinocytes. The EMBO journal 101 21909072
2014 Lipopolysaccharide (LPS) induces the apoptosis and inhibits osteoblast differentiation through JNK pathway in MC3T3-E1 cells. Inflammation 95 24272171
2005 Variation in IRF6 contributes to nonsyndromic cleft lip and palate. American journal of medical genetics. Part A 95 16096995
2019 Regulated Assembly of LPS, Its Structural Alterations and Cellular Response to LPS Defects. International journal of molecular sciences 94 30654491
2007 Association between IRF6 and nonsyndromic cleft lip with or without cleft palate in four populations. Genetics in medicine : official journal of the American College of Medical Genetics 92 17438386
2015 Salidroside attenuates lipopolysaccharide (LPS) induced serum cytokines and depressive-like behavior in mice. Neuroscience letters 85 26300543
2000 LPS and cytokine-activated endothelium. Seminars in thrombosis and hemostasis 81 11129414
2013 Smad4-Irf6 genetic interaction and TGFβ-mediated IRF6 signaling cascade are crucial for palatal fusion in mice. Development (Cambridge, England) 76 23406900
2019 The RIPK4-IRF6 signalling axis safeguards epidermal differentiation and barrier function. Nature 75 31578523
2000 Induction of proliferation and cytokine production in human T lymphocytes by lipopolysaccharide (LPS). Toxicology 69 11090938
1994 Bactericidal/permeability-increasing protein and lipopolysaccharide (LPS)-binding protein. LPS binding properties and effects on LPS-mediated cell activation. The Journal of biological chemistry 66 7517398
2020 Border Control: Regulating LPS Biogenesis. Trends in microbiology 60 33036869
2005 Phospholipids inhibit lipopolysaccharide (LPS)-induced cell activation: a role for LPS-binding protein. Journal of immunology (Baltimore, Md. : 1950) 60 15634934
2020 Lin28A promotes IRF6-regulated aerobic glycolysis in glioma cells by stabilizing SNHG14. Cell death & disease 59 32527996
2014 Differential and opposing effects of imatinib on LPS- and ventilator-induced lung injury. American journal of physiology. Lung cellular and molecular physiology 57 25480336
2003 Lipopolysaccharide (LPS)-binding protein inhibits responses to cell-bound LPS. The Journal of biological chemistry 56 12754215
2014 An etiologic regulatory mutation in IRF6 with loss- and gain-of-function effects. Human molecular genetics 55 24442519
2015 Cell rejuvenation and social behaviors promoted by LPS exchange in myxobacteria. Proceedings of the National Academy of Sciences of the United States of America 54 26038568
1994 Lipopolysaccharide (LPS) binding protein, truncated at Ile-197, binds LPS but does not transfer LPS to CD14. The Journal of biological chemistry 54 7510680
2009 New insight in LPS antagonist. Mini reviews in medicinal chemistry 52 19275723
2015 TLR3 drives IRF6-dependent IL-23p19 expression and p19/EBI3 heterodimer formation in keratinocytes. Immunology and cell biology 50 26303210
2012 Hepatic uptake and deacylation of the LPS in bloodborne LPS-lipoprotein complexes. Innate immunity 49 22441700
1994 LPS induces selective translocation of protein kinase C-beta in LPS-responsive mouse macrophages, but not in LPS-nonresponsive mouse macrophages. Journal of immunology (Baltimore, Md. : 1950) 49 7989773
2016 IRF6 Regulates the Expression of IL-36γ by Human Oral Epithelial Cells in Response to Porphyromonas gingivalis. Journal of immunology (Baltimore, Md. : 1950) 48 26819203
2015 IRF6 is the mediator of TGFβ3 during regulation of the epithelial mesenchymal transition and palatal fusion. Scientific reports 48 26240017
2009 Association between IRF6 SNPs and oral clefts in West China. Journal of dental research 47 19734457
2008 Effect of lipopolysaccharide (LPS) and peptidoglycan (PGN) on human mast cell numbers, cytokine production, and protease composition. BMC immunology 46 18687131
1995 LPS and Taxol activate Lyn kinase autophosphorylation in Lps(n), but not in Lpsd), macrophages. Molecular medicine (Cambridge, Mass.) 44 8521300
2022 Pinostrobin ameliorates lipopolysaccharide (LPS)-induced inflammation and endotoxemia by inhibiting LPS binding to the TLR4/MD2 complex. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 43 36270256
2012 Interaction between IRF6 and TGFA genes contribute to the risk of nonsyndromic cleft lip/palate. PloS one 43 23029012
1999 AVP inhibits LPS- and IL-1beta-stimulated NO and cGMP via V1 receptor in cultured rat mesangial cells. The American journal of physiology 42 10070167
2015 IRF6 mutation screening in non-syndromic orofacial clefting: analysis of 1521 families. Clinical genetics 41 26346622
2018 RNA-Seq transcriptomic profiling of primary murine microglia treated with LPS or LPS + IFNγ. Scientific reports 39 30382133
1993 Intracellular protein phosphorylation in murine peritoneal macrophages in response to bacterial lipopolysaccharide (LPS): effects of kinase-inhibitors and LPS-induced tolerance. Immunobiology 39 7687235
2011 MCS9.7 enhancer activity is highly, but not completely, associated with expression of Irf6 and p63. Developmental dynamics : an official publication of the American Association of Anatomists 38 22113860
2008 IRF6 in development and disease: a mediator of quiescence and differentiation. Cell cycle (Georgetown, Tex.) 38 18604160
2002 TLR4 and LPS hyporesponsiveness in humans. International journal of hygiene and environmental health 37 12040919
2014 Pretreatment of lipopolysaccharide (LPS) ameliorates D-GalN/LPS induced acute liver failure through TLR4 signaling pathway. International journal of clinical and experimental pathology 35 25400741
2019 Hydroxytyrosol Decreases LPS- and α-Synuclein-Induced Microglial Activation In Vitro. Antioxidants (Basel, Switzerland) 34 31906130
2017 Micheliolide suppresses LPS-induced neuroinflammatory responses. PloS one 33 29040306
2005 Non-LPS targets and actions of LPS binding protein (LBP). Journal of endotoxin research 33 16176661
2021 Dulaglutide Alleviates LPS-Induced Injury in Cardiomyocytes. ACS omega 31 33817486
2019 The TFAP2A-IRF6-GRHL3 genetic pathway is conserved in neurulation. Human molecular genetics 31 30689861
2017 Anti-inflammatory mechanism of lonchocarpine in LPS- or poly(I:C)-induced neuroinflammation. Pharmacological research 31 28288940
2014 LPS quantitation procedures. Methods in molecular biology (Clifton, N.J.) 31 24818921
1992 Mn and Cu/Zn SOD expression in cells from LPS-sensitive and LPS-resistant mice. Free radical biology & medicine 31 1559615
2017 Myricetin protects cardiomyocytes from LPS-induced injury. Herz 30 28357449
2017 Intercellular Genetic Interaction Between Irf6 and Twist1 during Craniofacial Development. Scientific reports 30 28769044
2012 Porphyromonas gingivalis LPS stimulates the expression of LPS-binding protein in human oral keratinocytes in vitro. Innate immunity 30 22736337
2003 Novel mutations in the IRF6 gene for Van der Woude syndrome. Human genetics 30 12920575
1995 Prolonged expression of lipopolysaccharide (LPS)-induced inflammatory genes in whole blood requires continual exposure to LPS. Infection and immunity 29 7890395
2012 LPS-binding protein enables intestinal epithelial restitution despite LPS exposure. Journal of pediatric gastroenterology and nutrition 27 22002480
1995 Lipopolysaccharide (LPS) binding protein catalyzes binding of LPS to lipoproteins. Progress in clinical and biological research 27 8524933
2020 An Irf6-Esrp1/2 regulatory axis controls midface morphogenesis in vertebrates. Development (Cambridge, England) 25 33234718
2017 IRF6 and SPRY4 Signaling Interact in Periderm Development. Journal of dental research 25 28732181
2010 ABCA1 promotes the efflux of bacterial LPS from macrophages and accelerates recovery from LPS-induced tolerance. Journal of lipid research 25 20472936
1998 Pulmonary LPS-binding protein (LBP) upregulation following LPS-mediated injury. The Journal of surgical research 25 9733616
2024 Plasticity-induced repression of Irf6 underlies acquired resistance to cancer immunotherapy in pancreatic ductal adenocarcinoma. Nature communications 24 38378697
2022 Sulforaphane diminishes moonlighting of pyruvate kinase M2 and interleukin 1β expression in M1 (LPS) macrophages. Frontiers in immunology 24 35983049
2020 SPECC1L regulates palate development downstream of IRF6. Human molecular genetics 24 31943082
2010 IRF6 Screening of Syndromic and a priori Non-Syndromic Cleft Lip and Palate Patients: Identification of a New Type of Minor VWS Sign. Molecular syndromology 24 21045959
2018 LPS Induces mTORC1 and mTORC2 Activation During Monocyte Adhesion. Frontiers in molecular biosciences 23 30073169
2002 Inhibition of LPS-induced activation of alveolar macrophages by high concentrations of LPS-binding protein. Biochemical and biophysical research communications 23 12150986
2020 TLR4 Response to LPS Is Reinforced by Urokinase Receptor. Frontiers in immunology 22 33362762
2017 IRF6 Regulates Alternative Activation by Suppressing PPARγ in Male Murine Macrophages. Endocrinology 22 28645193
2019 PBX-WNT-P63-IRF6 pathway in nonsyndromic cleft lip and palate. Birth defects research 21 31825181
2017 Disrupted IRF6-NME1/2 Complexes as a Cause of Cleft Lip/Palate. Journal of dental research 21 28767310
2004 A novel mutation of the IRF6 gene in an Italian family with Van der Woude syndrome. Mutation research 21 15013698
2003 Distinct LPS-induced signals regulate LPS uptake and morphological changes in medfly hemocytes. Insect biochemistry and molecular biology 21 14563359
2016 RIPK4 activates an IRF6-mediated proinflammatory cytokine response in keratinocytes. Cytokine 20 27014863
2013 Cell-autonomous and non-cell-autonomous roles for IRF6 during development of the tongue. PloS one 20 23451037

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