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IRF6  -  interferon regulatory factor 6

Homo sapiens

Synonyms: IRF-6, Interferon regulatory factor 6, LPS, OFC6, PIT, ...
 
 
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Disease relevance of IRF6

 

Psychiatry related information on IRF6

 

High impact information on IRF6

  • Mice deficient for Irf6 have not been reported, but in humans, mutations in IRF6 cause two mendelian orofacial clefting syndromes, and genetic variation in IRF6 confers risk for isolated cleft lip and palate [8].
  • Here, we show that mice carrying a homozygous missense mutation in interferon regulatory factor 6 (Irf6), the homolog of the gene mutated in the human congenital disorders Van der Woude syndrome and popliteal pterygium syndrome, have a hyperproliferative epidermis that fails to undergo terminal differentiation, resulting in soft tissue fusions [9].
  • Irf6 is a key determinant of the keratinocyte proliferation-differentiation switch [9].
  • We further demonstrate that mice that are compound heterozygotes for mutations in Irf6 and the gene encoding the cell cycle regulator protein stratifin (Sfn; also known as 14-3-3sigma) show similar defects of keratinizing epithelia [9].
  • Abnormal skin, limb and craniofacial morphogenesis in mice deficient for interferon regulatory factor 6 (Irf6) [8].
 

Chemical compound and disease context of IRF6

  • To determine the effects of increasing doses of prednisolone on inflammation and coagulation in humans exposed to LPS, 32 healthy males received prednisolone orally at doses of 0, 3, 10, or 30 mg (n = 8 per group) at 2 h before i.v. injection of Escherichia coli LPS (4 ng/kg) [10].
  • All of these LPS effects could be blocked by the Rho-GTPase inhibitor C3 transferase from Clostridium botulinum or the Rho kinase inhibitor Y-27632 [11].
  • Unlike Neisseria gonorrhoeae, binding of fH to N. meningitidis was independent of sialic acid on the bacterium, either as a component of its LPS or its capsule [12].
  • Peripheral blood monocytes isolated by centrifugal elutriation from healthy donors were incubated with rIFN-gamma and muramyl dipeptide, with a lipoprotein derived from Escherichia coli (CG-31362) or with LPS for 24 h [13].
  • To determine the effects of IL-10 on LPS-induced inflammatory responses, six Papio anubis baboons were i.v. injected with a sublethal dose of LPS (Salmonella typhimurium; 500 microg/kg) directly preceded by either human rIL-10 (n = 3, 500 microg/kg) or diluent (n = 3) [14].
 

Biological context of IRF6

  • Interferon regulatory factor 6 (IRF6) belongs to a family of nine transcription factors that share a highly conserved helix-turn-helix DNA-binding domain and a less conserved protein-binding domain [1].
  • The interaction occurs via the conserved IRF protein association domain and is regulated by phosphorylation of IRF6 [2].
  • These findings help to elucidate the molecular mechanisms of maspin and suggest an interactive role between maspin and IRF6 in regulating cellular phenotype, the loss of which can lead to neoplastic transformation [2].
  • We identified three missense mutations and one nonsense mutation in IRF6 [15].
  • To identify novel mutations of IRF6 in VWS patients, we screened four Chinese VWS families in all nine exons and their flanking splice junctions by direct sequencing [15].
 

Anatomical context of IRF6

  • Our observations demonstrate that haploinsufficiency of IRF6 disrupts orofacial development and are consistent with dominant-negative mutations disturbing development of the skin and genitalia [1].
  • We report that IRF6 is expressed in normal mammary epithelial cells and that it directly associates with maspin in a yeast two-hybrid system and in vitro [2].
  • The lethal toxicity and tolerance inducing properties of LPS are mediated by macrophages through tumor necrosis factor alpha (TNF alpha), which is probably the most important endogenous mediator of the lethal effects of LPS [16].
  • Here we show that a subset of human blood dendritic cells (DC) is the principal and primary source of IL-12p70 when blood leukocytes are stimulated with the TLR4-ligand LPS or with CD40-ligand [17].
  • In monocytes activated by either CE(sHUT) or LPS, the inhibition of PI3Ks abrogated sIL-1Ra transcript expression and sIL-1Ra production, demonstrating that PI3Ks control the induction of sIL-1Ra gene transcription [18].
 

Associations of IRF6 with chemical compounds

  • Because 25C>T and 250C>T predict to lead to R9W and R84C substitutions, respectively, at the most conserved DNA binding domain of IRF6, and because arginine at positions 9 and 84 is highly conserved among IRFs, the 2 mutations may lead to abolish the DNA binding activity in the developing craniofacial region [19].
  • Trafficking of TLR4 to lipid rafts in response to LPS was reactive oxygen species (ROS) dependent because it was inhibited by diphenylene iodonium, an inhibitor of NADPH oxidase, and in gp91(phox)-deficient macrophages [20].
  • In contrast, TNF-alpha-, LPS-, and integrin-induced NF-kappaB activation was not affected in Bcl10-deficient cells [21].
  • Stimulation of mPGES-1(-/-) VSMC and macrophages with bacterial LPS increased PGI(2) and thromboxane A(2) to varied extents [22].
  • Bacterial endotoxin (LPS)-induced synthesis of anandamide in macrophages is mediated exclusively by the PLC/phosphatase pathway, which is up-regulated by LPS, whereas NAPE-PLD is down-regulated by LPS and functions as a salvage pathway of anandamide synthesis when the PLC/phosphatase pathway is compromised [23].
 

Physical interactions of IRF6

  • Mammary serine protease inhibitor (Maspin) binds directly to interferon regulatory factor 6: identification of a novel serpin partnership [2].
  • LPS administered into experimental animals circulates as LPS/HDL complex and is cleared from the blood mainly into the liver and spleen [16].
  • Most interestingly, the association of LBP with LDL and VLDL strongly enhanced the capacity of these lipoproteins to bind LPS [24].
 

Regulatory relationships of IRF6

 

Other interactions of IRF6

  • Novel mutations in the IRF6 gene for Van der Woude syndrome [15].
  • Our study further confirmed that IRF6 is essential for craniofacial development [15].
  • In contrast to the IRF6 mutations reported in Caucasians, the majority of these mutations occurred at a run of 1- or 2-base repetitive sequence unit, and localized neither in the conserved DNA-binding domain nor in the Smad-interferon regulatory factor-binding domain (SMIR) [25].
  • [2005] in our large, well-characterized sample of NSCLP families and trios, and also detected an altered transmission of IRF6 alleles [26].
  • The manipulability, minimal cost and susceptibility of chicks to CL/P will enable more detailed investigations into how perturbations of IRF6, LHX6 and LHX7 contribute to common orofacial clefts [27].
 

Analytical, diagnostic and therapeutic context of IRF6

  • The number of neutrophils recovered from bronchoalveolar lavage after exposure to pulmonary LPS was significantly correlated with NF-kappaB activation in peripheral blood neutrophils obtained over the pre-LPS exposure period (r = 0.65, p = 0.009) [28].
  • Furthermore, TLR8 ligation inhibited LPS-induced IL-10 in monocytes, and LPS alone gained the ability to stimulate IL-12p70 in monocytes when the IL-10 receptor was blocked [29].
  • We established, using Northern blotting, nuclear run-on assays, and RT-PCR, that COX-2 transcriptional activation continues for at least 12 h after LPS treatment and involves at least three phases [30].
  • Quantitative microarray analysis of 4400 genes showed the same 30 genes were induced by BLP and LPS, and that there was near complete concordance in the level of gene induction [31].
  • Using electrophoretic mobility supershift and chromatin immunoprecipitation assays, we cataloged binding to each functional cis element and found them occupied to varying extents and by different transcription factors during the 12 h following LPS treatment [30].

References

  1. Mutations in IRF6 cause Van der Woude and popliteal pterygium syndromes. Kondo, S., Schutte, B.C., Richardson, R.J., Bjork, B.C., Knight, A.S., Watanabe, Y., Howard, E., de Lima, R.L., Daack-Hirsch, S., Sander, A., McDonald-McGinn, D.M., Zackai, E.H., Lammer, E.J., Aylsworth, A.S., Ardinger, H.H., Lidral, A.C., Pober, B.R., Moreno, L., Arcos-Burgos, M., Valencia, C., Houdayer, C., Bahuau, M., Moretti-Ferreira, D., Richieri-Costa, A., Dixon, M.J., Murray, J.C. Nat. Genet. (2002) [Pubmed]
  2. Mammary serine protease inhibitor (Maspin) binds directly to interferon regulatory factor 6: identification of a novel serpin partnership. Bailey, C.M., Khalkhali-Ellis, Z., Kondo, S., Margaryan, N.V., Seftor, R.E., Wheaton, W.W., Amir, S., Pins, M.R., Schutte, B.C., Hendrix, M.J. J. Biol. Chem. (2005) [Pubmed]
  3. Interferon regulatory factor-6: a gene predisposing to isolated cleft lip with or without cleft palate in the Belgian population. Ghassibé, M., Bayet, B., Revencu, N., Verellen-Dumoulin, C., Gillerot, Y., Vanwijck, R., Vikkula, M. Eur. J. Hum. Genet. (2005) [Pubmed]
  4. Interferon regulatory factor 6 (IRF6) gene variants and the risk of isolated cleft lip or palate. Zucchero, T.M., Cooper, M.E., Maher, B.S., Daack-Hirsch, S., Nepomuceno, B., Ribeiro, L., Caprau, D., Christensen, K., Suzuki, Y., Machida, J., Natsume, N., Yoshiura, K., Vieira, A.R., Orioli, I.M., Castilla, E.E., Moreno, L., Arcos-Burgos, M., Lidral, A.C., Field, L.L., Liu, Y.E., Ray, A., Goldstein, T.H., Schultz, R.E., Shi, M., Johnson, M.K., Kondo, S., Schutte, B.C., Marazita, M.L., Murray, J.C. N. Engl. J. Med. (2004) [Pubmed]
  5. Apolipoproteins modulate the inflammatory response to lipopolysaccharide. Berbée, J.F., Havekes, L.M., Rensen, P.C. J. Endotoxin Res. (2005) [Pubmed]
  6. The effect of prospective payment on rehabilitative care. Dobrez, D.G., Lo Sasso, A.T., Heinemann, A.W. Archives of physical medicine and rehabilitation. (2004) [Pubmed]
  7. Relations between body composition, functional and hormonal parameters and quality of life in healthy postmenopausal women. Lebrun, C.E., van der Schouw, Y.T., de Jong, F.H., Pols, H.A., Grobbee, D.E., Lamberts, S.W. Maturitas. (2006) [Pubmed]
  8. Abnormal skin, limb and craniofacial morphogenesis in mice deficient for interferon regulatory factor 6 (Irf6). Ingraham, C.R., Kinoshita, A., Kondo, S., Yang, B., Sajan, S., Trout, K.J., Malik, M.I., Dunnwald, M., Goudy, S.L., Lovett, M., Murray, J.C., Schutte, B.C. Nat. Genet. (2006) [Pubmed]
  9. Irf6 is a key determinant of the keratinocyte proliferation-differentiation switch. Richardson, R.J., Dixon, J., Malhotra, S., Hardman, M.J., Knowles, L., Boot-Handford, R.P., Shore, P., Whitmarsh, A., Dixon, M.J. Nat. Genet. (2006) [Pubmed]
  10. Prednisolone Dose-Dependently Influences Inflammation and Coagulation during Human Endotoxemia. de Kruif, M.D., Lemaire, L.C., Giebelen, I.A., van Zoelen, M.A., Pater, J.M., van den Pangaart, P.S., Groot, A.P., de Vos, A.F., Elliott, P.J., Meijers, J.C., Levi, M., van der Poll, T. J. Immunol. (2007) [Pubmed]
  11. Cyclic AMP blocks bacterial lipopolysaccharide-induced myosin light chain phosphorylation in endothelial cells through inhibition of Rho/Rho kinase signaling. Essler, M., Staddon, J.M., Weber, P.C., Aepfelbacher, M. J. Immunol. (2000) [Pubmed]
  12. Functional significance of factor H binding to Neisseria meningitidis. Schneider, M.C., Exley, R.M., Chan, H., Feavers, I., Kang, Y.H., Sim, R.B., Tang, C.M. J. Immunol. (2006) [Pubmed]
  13. Tumor necrosis factor and IL-1 associated with plasma membranes of activated human monocytes lyse monokine-sensitive but not monokine-resistant tumor cells whereas viable activated monocytes lyse both. Ichinose, Y., Bakouche, O., Tsao, J.Y., Fidler, I.J. J. Immunol. (1988) [Pubmed]
  14. Effects of IL-10 on systemic inflammatory responses during sublethal primate endotoxemia. van der Poll, T., Jansen, P.M., Montegut, W.J., Braxton, C.C., Calvano, S.E., Stackpole, S.A., Smith, S.R., Swanson, S.W., Hack, C.E., Lowry, S.F., Moldawer, L.L. J. Immunol. (1997) [Pubmed]
  15. Novel mutations in the IRF6 gene for Van der Woude syndrome. Wang, X., Liu, J., Zhang, H., Xiao, M., Li, J., Yang, C., Lin, X., Wu, Z., Hu, L., Kong, X. Hum. Genet. (2003) [Pubmed]
  16. Bacterial lipopolysaccharides: structure, metabolism and mechanisms of action. Freudenberg, M.A., Galanos, C. Int. Rev. Immunol. (1990) [Pubmed]
  17. Human 6-sulfo LacNAc-expressing dendritic cells are principal producers of early interleukin-12 and are controlled by erythrocytes. Schäkel, K., von Kietzell, M., Hänsel, A., Ebling, A., Schulze, L., Haase, M., Semmler, C., Sarfati, M., Barclay, A.N., Randolph, G.J., Meurer, M., Rieber, E.P. Immunity (2006) [Pubmed]
  18. Opposite Regulation of IL-1beta and Secreted IL-1 Receptor Antagonist Production by Phosphatidylinositide-3 Kinases in Human Monocytes Activated by Lipopolysaccharides or Contact with T Cells. Molnarfi, N., Gruaz, L., Dayer, J.M., Burger, D. J. Immunol. (2007) [Pubmed]
  19. Two missense mutations in the IRF6 gene in two Japanese families with Van der Woude syndrome. Matsuzawa, N., Yoshiura, K., Machida, J., Nakamura, T., Niimi, T., Furukawa, H., Toyoda, T., Natsume, N., Shimozato, K., Niikawa, N. Oral surgery, oral medicine, oral pathology, oral radiology, and endodontics. (2004) [Pubmed]
  20. Carbon monoxide differentially inhibits TLR signaling pathways by regulating ROS-induced trafficking of TLRs to lipid rafts. Nakahira, K., Kim, H.P., Geng, X.H., Nakao, A., Wang, X., Murase, N., Drain, P.F., Wang, X., Sasidhar, M., Nabel, E.G., Takahashi, T., Lukacs, N.W., Ryter, S.W., Morita, K., Choi, A.M. J. Exp. Med. (2006) [Pubmed]
  21. Bcl10 plays a critical role in NF-{kappa}B activation induced by G protein-coupled receptors. Wang, D., You, Y., Lin, P.C., Xue, L., Morris, S.W., Zeng, H., Wen, R., Lin, X. Proc. Natl. Acad. Sci. U.S.A. (2007) [Pubmed]
  22. Deletion of microsomal prostaglandin E synthase-1 augments prostacyclin and retards atherogenesis. Wang, M., Zukas, A.M., Hui, Y., Ricciotti, E., Pur??, E., Fitzgerald, G.A. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  23. A biosynthetic pathway for anandamide. Liu, J., Wang, L., Harvey-White, J., Osei-Hyiaman, D., Razdan, R., Gong, Q., Chan, A.C., Zhou, Z., Huang, B.X., Kim, H.Y., Kunos, G. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  24. LPS-binding protein circulates in association with apoB-containing lipoproteins and enhances endotoxin-LDL/VLDL interaction. Vreugdenhil, A.C., Snoek, A.M., van 't Veer, C., Greve, J.W., Buurman, W.A. J. Clin. Invest. (2001) [Pubmed]
  25. Identification of novel mutations of IRF6 gene in Chinese families with Van der Woude syndrome. Ye, X.Q., Jin, H.X., Shi, L.S., Fan, M.W., Song, G.T., Fan, H.L., Bian, Z. Int. J. Mol. Med. (2005) [Pubmed]
  26. Variation in IRF6 contributes to nonsyndromic cleft lip and palate. Blanton, S.H., Cortez, A., Stal, S., Mulliken, J.B., Finnell, R.H., Hecht, J.T. Am. J. Med. Genet. A (2005) [Pubmed]
  27. Expression profiles of cIRF6, cLHX6 and cLHX7 in the facial primordia suggest specific roles during primary palatogenesis. Washbourne, B.J., Cox, T.C. BMC Dev. Biol. (2006) [Pubmed]
  28. Peripheral blood neutrophil activation patterns are associated with pulmonary inflammatory responses to lipopolysaccharide in humans. Abraham, E., Nick, J.A., Azam, T., Kim, S.H., Mira, J.P., Svetkauskaite, D., He, Q., Zamora, M., Murphy, J., Park, J.S., Overdier, K., Dinarello, C.A. J. Immunol. (2006) [Pubmed]
  29. T cell-independent, TLR-induced IL-12p70 production in primary human monocytes. Bekeredjian-Ding, I., Roth, S.I., Gilles, S., Giese, T., Ablasser, A., Hornung, V., Endres, S., Hartmann, G. J. Immunol. (2006) [Pubmed]
  30. Cyclooxygenase-2 gene transcription in a macrophage model of inflammation. Kang, Y.J., Wingerd, B.A., Arakawa, T., Smith, W.L. J. Immunol. (2006) [Pubmed]
  31. Escherichia coli Braun lipoprotein induces a lipopolysaccharide-like endotoxic response from primary human endothelial cells. Neilsen, P.O., Zimmerman, G.A., McIntyre, T.M. J. Immunol. (2001) [Pubmed]
 
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