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

• Together, psoriasis is not associated with a promoter polymorphism in the IL12B gene nor with the production of IL-12p70 by LPS-stimulated blood cells [7].
• Finally, unlike IL-12 p40 mRNA, the constitutive accumulation of IL-18 transcripts by unstimulated cells was amplified in the presence of the translational blocker cycloheximide, which also caused a superinduction of IL-18 expression after Staphylococcus aureus stimulation [8].

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

• Using an IL-12 p40-specific radioimmunoassay (RIA), we confirmed the presence of IL-12 in IL-2 plus retinoid-treated culture supernatants [16].
• Here we present evidence that histamine, at physiological concentrations, strongly inhibits human IL-12 p40 and p70 mRNA and protein production by human monocytes [17].
• Here, we studied IL-12 p40 and p70 production in relation to IL-10 and PGE2 production in whole blood cultures from HIV-infected individuals [18].
• ERK pathway inhibitors increased expression of major histocompatibility complex and costimulatory molecules; loss of mannose-receptor-mediated endocytic activity; nuclear factor-kappaB DNA-binding activity; release of IL-12 p40; and allogeneic T-cell proliferation induced by LPS or TNF-alpha [19].
• The TNFalpha inhibitor rolipram inhibited LPS-stimulated IL-12 p40 production by RA SC more strongly than spontaneous production [20].

Physical interactions of IL12B

• Human IL-12 p40 homodimer binds to the IL-12 receptor but does not mediate biologic activity [21].

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

• METHODS: We did a cohort study in which we initially genotyped 411 6-year olds for the IL12B promoter polymorphism [32].
• RESULTS: Elevated plasma levels of IFN-gamma and of IL-12 p40 were observed during active disease, significantly decreasing after treatment whereas in vitro Leishmania antigen-stimulated IFN-gamma production by PBMC exhibited an inverse pattern being low during disease and increasing steadily thereafter [33].
• Homozygotes for the IL12B promoter polymorphism showed a 10-fold difference in median p70 secretion in response to CD40 ligation [13].
• We found expression of IL-12 p40 mRNA, as measured by PCR amplification, and IL-12 p70, as measured by immunohistochemistry, to be 10-fold greater in tuberculoid lesions than in lepromatous lesions [34].
• Enzyme-linked immunosorbent assay and reverse transcriptase polymerase chain reaction analysis were used to detect IL-12 p40 protein level and mRNA transcription, respectively [24].

References