Abstract
Interleukin-12 (IL-12) is a key cytokine for the induction of Th1 immune responses. We evaluated whether a TaqI polymorphism in the 3′UTR of the IL-12 p40 gene affects secretion of IL-12 in vitro, and whether this polymorphism is associated with susceptibility to Crohn's disease (CD). IL-12 p40 and p70 secretion by monocytes in relation to genotype was determined in 63 healthy donors. Genotype and allele frequencies of the TaqI polymorphism in 150 CD patients were compared with 145 ethnically matched healthy controls (HC). No significant association was found between genotype and IL-12 p40 secretion after stimulation of monocytes with SAC+IFNγ. In contrast, increasing IL-12 p70 secretion was found across the categories of non-carriers, heterozygotes and homozygotes for the variant allele (median values±SEM: 147±27, 282±51 and 482±34 pg/ml, respectively; P<0.005). The allele and genotype frequencies of this polymorphism in patients with CD did not differ statistically significantly from HC. The presence of a TaqI polymorphism in the IL12 p40 3′UTR correlates with increased in vitro IL-12 p70, but not p40 secretion. While this polymorphism does not appear to be correlated with susceptibility to CD in the limited population of patients tested here, it could influence the occurrence of the disease in certain subsets of patients.
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References
Gately MK, Renzetti LM, Magram J et al. The interleukin-12/interleukin-12-receptor system: role in normal and pathologic immune responses Annu Rev Immunol 1998 16: 495–521
Heufler C, Koch F, Stanzl U et al. Interleukin-12 is produced by dendritic cells and mediates T helper 1 development as well as interferon-gamma production by T helper 1 cells Eur J Immunol 1996 26: 659–668
Koch F, Stanzl U, Jennewein P et al. High level IL-12 production by murine dendritic cells: upregulation via MHC class II and CD40 molecules and downregulation by IL-4 and IL-10 J Exp Med 1996 184: 741–746
Ebner S, Ratzinger G, Krosbacher B et al. Production of IL-12 by human monocyte-derived dendritic cells is optimal when the stimulus is given at the onset of maturation, and is further enhanced by IL-4 J Immunol 2001 166: 633–641
Morita Y, Yamamura M, Nishida K et al. Expression of interleukin-12 in synovial tissue from patients with rheumatoid arthritis Arthritis Rheum 1998 41: 306–314
Adorini L . Interleukin 12 and autoimmune diabetes Nat Genet 2001 27: 131–132
Windhagen A, Newcombe J, Dangond F et al. Expression of costimulatory molecules B7-1 (CD80), B7-2 (CD86), and interleukin 12 cytokine in multiple sclerosis lesions J Exp Med 1995 182: 1985–1996
Monteleone G, Biancone L, Marasco R et al. Interleukin 12 is expressed and actively released by Crohn's disease intestinal lamina propria mononuclear cells Gastroenterology 1997 112: 1169–1178
Picard C, Fieschi C, Altare F et al. Inherited interleukin-12 deficiency: IL12B genotype and clinical phenotype of 13 patients from six kindreds Am J Hum Genet 2002 70: 336–348
Altare F, Durandy A, Lammas D et al. Impairment of mycobacterial immunity in human interleukin-12 receptor deficiency Science 1998 280: 1432–1435
Neurath MF, Fuss I, Kelsall BL, Stuber E, Strober W . Antibodies to interleukin 12 abrogate established experimental colitis in mice J Exp Med 1996 182: 1281–1290
Bouma G, Kaushiva A, Strober W . Identification of a genetic region that regulates susceptibility to experimental murine colitis and the interleukin-12 response to LPS Gastroenterology 2002 123: 554–565
Sieburth D, Jabs EW, Warrington JA et al. Assignment of genes encoding a unique cytokine (IL12) composed of two unrelated subunits to chromosomes 3 and 5 Genomics 1992 14: 59–62
Huang D, Cancilla MR, Morahan G . Complete primary structure, chromosomal localisation, and definition of polymorphisms of the gene encoding the human interleukin-12 p40 subunit Genes Immun 2000 1: 515–520
Le Cam A, Legraverend C . Transcriptional repression, a novel function for 3′ untranslated regions Eur J Biochem 1995 231: 620–627
Grzybowska EA, Wilczynska A, Siedlecki JA . Regulatory functions of 3'UTRs Biochem Biophys Res Commun 2001 288: 291–295
van Veen T, Crusius JB, Schrijver HM et al. Interleukin-12p40 genotype plays a role in the susceptibility to multiple sclerosis Ann Neurol 2001 50: 275
Morahan G, Huang D, Ymer SI et al. Linkage disequilibrium of a type 1 diabetes susceptibility locus with a regulatory IL12B allele Nat Genet 2001 27: 218–221
Heinzel FP, Hujer AM, Ahmed FN, Rerko RM . In vivo production and function of IL-12 p40 homodimers J Immunol 1997 158: 4381–4388
Yoon C, Johnston SC, Tang J et al. Charged residues dominate a unique interlocking topography in the heterodimeric cytokine interleukin-12 Embo J 2000 19: 3530–3541
Ymer SI, Huang D, Penna G et al. Polymorphisms in the IL12b gene affect structure and expression of IL-12 in NOD and other autoimmune-prone strains Genes Immun 2002 3: 151–157
Hugot JP, Chamaillard M, Zouali H et al. Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease Nature 2001 411: 599–603
Ogura Y, Bonen DK, Inohara N et al. A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease Nature 2001 411: 603–606
Dahlman I, Eaves IA, Kosoy R et al. Parameters for reliable results in genetic association studies in common disease Nat Genet 2002 30: 149–150
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G Bouma is a fellow of the Royal Dutch Academy of Sciences. This work was supported in part by a grant from the Crohn's and Colitis Foundation of America.
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Seegers, D., Zwiers, A., Strober, W. et al. A TaqI polymorphism in the 3′UTR of the IL-12 p40 gene correlates with increased IL-12 secretion. Genes Immun 3, 419–423 (2002). https://doi.org/10.1038/sj.gene.6363919
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DOI: https://doi.org/10.1038/sj.gene.6363919
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