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IL12B  -  interleukin 12B (natural killer cell...

Homo sapiens

 
 
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Disease relevance of IL12B

  • Haplotypes were estimated, and genotype-conditioned analyses identified a second risk allele (rs6887695) located ~60 kb upstream of the IL12B coding region that exhibited association with psoriasis after adjustment for rs3212227 [1].
  • Influence of interleukin 12B (IL12B) polymorphisms on spontaneous and treatment-induced recovery from hepatitis C virus infection [2].
  • However, HCV genotype 1-infected patients with high baseline viremia carrying the IL12B 3'-UTR 1188-C-allele showed significantly higher sustained virologic response (SVR) rates (25.3% vs. 46% vs. 54.5% for A/A, A/C and C/C) due to reduced relapse rates (24.2% vs. 12% vs. zero % for A/A, A/C and C/C) [2].
  • Similarly, variation in IL12B might be involved in susceptibility to Crohn's disease (CD), a chronic inflammatory bowel disorder associated with high IL-12 expression [3].
  • Recently, functional polymorphisms in IL-12p40 (IL12B) were found to be associated with susceptibility to several autoimmune diseases [3].
 

High impact information on IL12B

  • The M55V substitution resulted in 5.5 times greater NF kappa B transcriptional activity and approximately 2 times greater expression of IL12B, an NF kappa B-dependent gene [4].
  • We report here a new susceptibility locus, IDDM18, located near the interleukin-12 (IL-12)p40 gene, IL12B [5].
  • The IL12B 3' UTR alleles showed different levels of expression in cell lines [5].
  • Linkage disequilibrium of a type 1 diabetes susceptibility locus with a regulatory IL12B allele [5].
  • Moreover, NKSF strongly inhibited IL-2-induced proliferation of either resting or preactivated NK cells [6].
 

Chemical compound and disease context of IL12B

 

Biological context of IL12B

  • Together, these two SNPs mark a common IL12B risk haplotype (OR(common) 1.40, Pcomb=8.11x10-9) and a less frequent protective haplotype (OR(common) 0.58, Pcomb=5.65x10-12), which were statistically significant in all three studies [1].
  • The IL12B gene on chromosome 5q31-33 encodes the p40 subunit of interleukin 12, an immunomodulatory cytokine [9].
  • Inherited interleukin-12 deficiency: IL12B genotype and clinical phenotype of 13 patients from six kindreds [10].
  • A conserved haplotype encompassing the IL12B gene suggested that a founder effect accounted for the recurrence of each mutation [10].
  • RESULTS: The IL12B genotypes were not associated with asthma susceptibility, severity, or atopy at ages 7 and 42 years [11].
 

Anatomical context of IL12B

  • No association was observed between the various IL12B promoter genotypes and the LPS-stimulated production of IL-12p70 or IL-12p40 by blood cells [7].
  • We have previously delineated a common deleted region of 5.6 Mb between the gene for fibroblast growth factor acidic (FGF1) and the subunit of interleukin 12 (IL12B) in two patients with 5q- syndrome and small deletions, del(5)(q31q33) [12].
  • Deficient IL-12p70 secretion by dendritic cells based on IL12B promoter genotype [13].
  • A large homozygous deletion within the IL-12 p40 subunit gene was found, precluding expression of functional IL-12 p70 cytokine by activated dendritic cells and phagocytes [14].
  • The GCS-induced changes in IL-12 and IL-10 occurred in monocytes, and involved changes in IL-12 p40 and IL-10 mRNA expression [15].
 

Associations of IL12B with chemical compounds

 

Physical interactions of IL12B

 

Regulatory relationships of IL12B

  • Moreover, CD154-induced IL-12 p40 expression is enhanced after blockade of NOS-3 activity but attenuated in the presence of exogenous nitric oxide [22].
  • TNF-alpha selectively inhibits IL-12 p40 steady-state mRNA, but not those of IL-12 p35, IL-1alpha, IL-1beta, or IL-6 [23].
  • IL-12 p40 production and mRNA transcription were also inhibited in DC both by TII and by IL-10 [24].
  • RESULTS: Synovial tissues from RA patients more strongly expressed IL-12 p40 mRNA than did OA tissues [25].
  • NKSF regulates IFN-gamma mRNA expression in PHA blasts and the T leukemia cell line, TALL-103/2, at both the transcriptional and posttranscriptional levels [26].
 

Other interactions of IL12B

  • Further associations were observed with single nucleotide polymorphisms (SNPs) at the IL2 and IL4 loci along with insertion/deletion variants at the IL12B locus (P =.003-.01) [27].
  • Furthermore, ELISA showed that secretions of TNF-alpha and IL-12 p40, but not IL-10, were induced in iDC by the costimulation [28].
  • IL-6 and IL-12 p40 mRNA were detected in approximately one-half of the patients [29].
  • Complete IL-12 p40 and IL-12 receptor beta1 deficiencies and partial IFNgamma receptor 1 (IFNgammaR1) and IFNgammaR2 deficiencies generally lead to curable infections at various ages, and antibiotics supplemented with IFNgamma if required are likely to be effective [30].
  • We have mapped this gene to the 3 Mb critical region of gene loss of the 5q- syndrome within 5q32, flanked by the genes for ADRB2 and IL12B, using gene dosage analysis [31].
 

Analytical, diagnostic and therapeutic context of IL12B

References

  1. A Large-Scale Genetic Association Study Confirms IL12B and Leads to the Identification of IL23R as Psoriasis-Risk Genes. Cargill, M., Schrodi, S.J., Chang, M., Garcia, V.E., Brandon, R., Callis, K.P., Matsunami, N., Ardlie, K.G., Civello, D., Catanese, J.J., Leong, D.U., Panko, J.M., McAllister, L.B., Hansen, C.B., Papenfuss, J., Prescott, S.M., White, T.J., Leppert, M.F., Krueger, G.G., Begovich, A.B. Am. J. Hum. Genet. (2007) [Pubmed]
  2. Influence of interleukin 12B (IL12B) polymorphisms on spontaneous and treatment-induced recovery from hepatitis C virus infection. Mueller, T., Mas-Marques, A., Sarrazin, C., Wiese, M., Halangk, J., Witt, H., Ahlenstiel, G., Spengler, U., Goebel, U., Wiedenmann, B., Schreier, E., Berg, T. J. Hepatol. (2004) [Pubmed]
  3. Definition of polymorphisms and haplotypes in the interleukin-12B gene: association with IL-12 production but not with Crohn's disease. Zwiers, A., Seegers, D., Heijmans, R., Koch, A., Hampe, J., Nikolaus, S., Peña, A.S., Schreiber, S., Bouma, G. Genes Immun. (2004) [Pubmed]
  4. A functional variant of SUMO4, a new I kappa B alpha modifier, is associated with type 1 diabetes. Guo, D., Li, M., Zhang, Y., Yang, P., Eckenrode, S., Hopkins, D., Zheng, W., Purohit, S., Podolsky, R.H., Muir, A., Wang, J., Dong, Z., Brusko, T., Atkinson, M., Pozzilli, P., Zeidler, A., Raffel, L.J., Jacob, C.O., Park, Y., Serrano-Rios, M., Larrad, M.T., Zhang, Z., Garchon, H.J., Bach, J.F., Rotter, J.I., She, J.X., Wang, C.Y. Nat. Genet. (2004) [Pubmed]
  5. Linkage disequilibrium of a type 1 diabetes susceptibility locus with a regulatory IL12B allele. Morahan, G., Huang, D., Ymer, S.I., Cancilla, M.R., Stephen, K., Dabadghao, P., Werther, G., Tait, B.D., Harrison, L.C., Colman, P.G. Nat. Genet. (2001) [Pubmed]
  6. Response of human natural killer (NK) cells to NK cell stimulatory factor (NKSF): cytolytic activity and proliferation of NK cells are differentially regulated by NKSF. Robertson, M.J., Soiffer, R.J., Wolf, S.F., Manley, T.J., Donahue, C., Young, D., Herrmann, S.H., Ritz, J. J. Exp. Med. (1992) [Pubmed]
  7. Psoriasis is not associated with IL-12p70/IL-12p40 production and IL12B promoter polymorphism. Litjens, N.H., van der Plas, M.J., Ravensbergen, B., Numan-Ruberg, S.C., van Assen, Y., Thio, H.B., van Dissel, J.T., van de Vosse, E., Nibbering, P.H. J. Invest. Dermatol. (2004) [Pubmed]
  8. Regulation of human IL-18 mRNA expression. Marshall, J.D., Aste-Amézaga, M., Chehimi, S.S., Murphy, M., Olsen, H., Trinchieri, G. Clin. Immunol. (1999) [Pubmed]
  9. The IL12B gene is associated with asthma. Randolph, A.G., Lange, C., Silverman, E.K., Lazarus, R., Silverman, E.S., Raby, B., Brown, A., Ozonoff, A., Richter, B., Weiss, S.T. Am. J. Hum. Genet. (2004) [Pubmed]
  10. Inherited interleukin-12 deficiency: IL12B genotype and clinical phenotype of 13 patients from six kindreds. Picard, C., Fieschi, C., Altare, F., Al-Jumaah, S., Al-Hajjar, S., Feinberg, J., Dupuis, S., Soudais, C., Al-Mohsen, I.Z., Génin, E., Lammas, D., Kumararatne, D.S., Leclerc, T., Rafii, A., Frayha, H., Murugasu, B., Wah, L.B., Sinniah, R., Loubser, M., Okamoto, E., Al-Ghonaium, A., Tufenkeji, H., Abel, L., Casanova, J.L. Am. J. Hum. Genet. (2002) [Pubmed]
  11. Associations of the IL12B promoter polymorphism in longitudinal data from asthmatic patients 7 to 42 years of age. Khoo, S.K., Hayden, C.M., Roberts, M., Horak, E., de Klerk, N., Zhang, G., Robertson, C.F., Goldblatt, J., Le Souëf, P. J. Allergy Clin. Immunol. (2004) [Pubmed]
  12. Molecular cytogenetic delineation of the critical deleted region in the 5q- syndrome. Jaju, R.J., Boultwood, J., Oliver, F.J., Kostrzewa, M., Fidler, C., Parker, N., McPherson, J.D., Morris, S.W., Müller, U., Wainscoat, J.S., Kearney, L. Genes Chromosomes Cancer (1998) [Pubmed]
  13. Deficient IL-12p70 secretion by dendritic cells based on IL12B promoter genotype. Müller-Berghaus, J., Kern, K., Paschen, A., Nguyen, X.D., Klüter, H., Morahan, G., Schadendorf, D. Genes Immun. (2004) [Pubmed]
  14. Inherited interleukin 12 deficiency in a child with bacille Calmette-Guérin and Salmonella enteritidis disseminated infection. Altare, F., Lammas, D., Revy, P., Jouanguy, E., Döffinger, R., Lamhamedi, S., Drysdale, P., Scheel-Toellner, D., Girdlestone, J., Darbyshire, P., Wadhwa, M., Dockrell, H., Salmon, M., Fischer, A., Durandy, A., Casanova, J.L., Kumararatne, D.S. J. Clin. Invest. (1998) [Pubmed]
  15. Human glioma-induced immunosuppression involves soluble factor(s) that alters monocyte cytokine profile and surface markers. Zou, J.P., Morford, L.A., Chougnet, C., Dix, A.R., Brooks, A.G., Torres, N., Shuman, J.D., Coligan, J.E., Brooks, W.H., Roszman, T.L., Shearer, G.M. J. Immunol. (1999) [Pubmed]
  16. Retinoids synergize with interleukin-2 to augment IFN-gamma and interleukin-12 production by human peripheral blood mononuclear cells. Fox, F.E., Kubin, M., Cassin, M., Niu, Z., Trinchieri, G., Cooper, K.D., Rook, A.H. J. Interferon Cytokine Res. (1999) [Pubmed]
  17. Histamine inhibits the production of interleukin-12 through interaction with H2 receptors. van der Pouw Kraan, T.C., Snijders, A., Boeije, L.C., de Groot, E.R., Alewijnse, A.E., Leurs, R., Aarden, L.A. J. Clin. Invest. (1998) [Pubmed]
  18. Interleukin-12 (IL-12) production in whole blood cultures from human immunodeficiency virus-infected individuals studied in relation to IL-10 and prostaglandin E2 production. Meyaard, L., Hovenkamp, E., Pakker, N., van der Pouw Kraan, T.C., Miedema, F. Blood (1997) [Pubmed]
  19. Extracellular signal-regulated protein kinase signaling pathway negatively regulates the phenotypic and functional maturation of monocyte-derived human dendritic cells. Puig-Kröger, A., Relloso, M., Fernández-Capetillo, O., Zubiaga, A., Silva, A., Bernabéu, C., Corbí, A.L. Blood (2001) [Pubmed]
  20. Differential regulation of rheumatoid synovial cell interleukin-12 production by tumor necrosis factor alpha and CD40 signals. Kitagawa, M., Mitsui, H., Nakamura, H., Yoshino, S., Miyakawa, S., Ochiai, N., Onobori, M., Suzuki, H., Sumida, T. Arthritis Rheum. (1999) [Pubmed]
  21. Human IL-12 p40 homodimer binds to the IL-12 receptor but does not mediate biologic activity. Ling, P., Gately, M.K., Gubler, U., Stern, A.S., Lin, P., Hollfelder, K., Su, C., Pan, Y.C., Hakimi, J. J. Immunol. (1995) [Pubmed]
  22. Interleukin-10 induction of nitric-oxide synthase expression attenuates CD40-mediated interleukin-12 synthesis in human endothelial cells. Cattaruzza, M., Słodowski, W., Stojakovic, M., Krzesz, R., Hecker, M. J. Biol. Chem. (2003) [Pubmed]
  23. Inhibition of IL-12 production in human monocyte-derived macrophages by TNF. Ma, X., Sun, J., Papasavvas, E., Riemann, H., Robertson, S., Marshall, J., Bailer, R.T., Moore, A., Donnelly, R.P., Trinchieri, G., Montaner, L.J. J. Immunol. (2000) [Pubmed]
  24. Effects of Tripterygium wilfordii saponins and interleukin-10 on dendritic cells from human peripheral blood. Wang, S.J., Yao, K., Xie, F.D., Ji, X.H. Acta Pharmacol. Sin. (2001) [Pubmed]
  25. Expression of interleukin-12 in synovial tissue from patients with rheumatoid arthritis. Morita, Y., Yamamura, M., Nishida, K., Harada, S., Okamoto, H., Inoue, H., Ohmoto, Y., Modlin, R.L., Makino, H. Arthritis Rheum. (1998) [Pubmed]
  26. Mechanisms of IFN-gamma induction by natural killer cell stimulatory factor (NKSF/IL-12). Role of transcription and mRNA stability in the synergistic interaction between NKSF and IL-2. Chan, S.H., Kobayashi, M., Santoli, D., Perussia, B., Trinchieri, G. J. Immunol. (1992) [Pubmed]
  27. HLA and cytokine gene polymorphisms are independently associated with responses to hepatitis B vaccination. Wang, C., Tang, J., Song, W., Lobashevsky, E., Wilson, C.M., Kaslow, R.A. Hepatology (2004) [Pubmed]
  28. Lipoteichoic acid and muramyl dipeptide synergistically induce maturation of human dendritic cells and concurrent expression of proinflammatory cytokines. Kim, H.J., Yang, J.S., Woo, S.S., Kim, S.K., Yun, C.H., Kim, K.K., Han, S.H. J. Leukoc. Biol. (2007) [Pubmed]
  29. In vivo gene expression of type 1 and type 2 cytokines in synovial tissues from patients in early stages of rheumatoid, reactive, and undifferentiated arthritis. Kotake, S., Schumacher, H.R., Yarboro, C.H., Arayssi, T.K., Pando, J.A., Kanik, K.S., Gourley, M.F., Klippel, J.H., Wilder, R.L. Proc. Assoc. Am. Physicians (1997) [Pubmed]
  30. Impaired interferon gamma-mediated immunity and susceptibility to mycobacterial infection in childhood. Remus, N., Reichenbach, J., Picard, C., Rietschel, C., Wood, P., Lammas, D., Kumararatne, D.S., Casanova, J.L. Pediatr. Res. (2001) [Pubmed]
  31. Physical mapping of the human ATX1 homologue (HAH1) to the critical region of the 5q- syndrome within 5q32, and immediately adjacent to the SPARC gene. Boultwood, J., Strickson, A.J., Jabs, E.W., Cheng, J.F., Fidler, C., Wainscoat, J.S. Hum. Genet. (2000) [Pubmed]
  32. Association of IL12B promoter polymorphism with severity of atopic and non-atopic asthma in children. Morahan, G., Huang, D., Wu, M., Holt, B.J., White, G.P., Kendall, G.E., Sly, P.D., Holt, P.G. Lancet (2002) [Pubmed]
  33. Balance of IL-10 and Interferon-gamma plasma levels in human visceral leishmaniasis: implications in the pathogenesis. Caldas, A., Favali, C., Aquino, D., Vinhas, V., van Weyenbergh, J., Brodskyn, C., Costa, J., Barral-Netto, M., Barral, A. BMC Infect. Dis. (2005) [Pubmed]
  34. IL-12 regulates T helper type 1 cytokine responses in human infectious disease. Sieling, P.A., Wang, X.H., Gately, M.K., Oliveros, J.L., McHugh, T., Barnes, P.F., Wolf, S.F., Golkar, L., Yamamura, M., Yogi, Y. J. Immunol. (1994) [Pubmed]
 
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