The influence of JNK and P38 MAPK inhibition on IL-12P40 and IL-23 production depending on IL12B promoter polymorphism

Abstract

Abstract:The interleukin-12p40 gene (IL12B) encodes the p40 polypeptide chain, which, together with p19, composes IL-23. A bi-allelic promoter polymorphism (IL12Bpro) located at -2703 bp of the transcription initiation site has been reported to show associations with IL-12p40 production. To elucidate the dependence of IL-12p40 and IL-23 production on IL12Bpro polymorphism in relation to MAPK signal transduction pathways, we examined the effect of JNK and p38 inhibition on the secretion of these cytokines by stimulated peripheral blood mononuclear cells (PBMC) from healthy donors with 1.1 and 1.2/2.2 IL12Bpro genotypes. Stimulation with LPS and C3bgp resulted in approximately equal IL-12p40 production from PBMC with the 1.1 and 1.2/2.2 genotypes. The inhibition of JNK and p38 before stimulation significantly upregulated IL-12p40 production by PBMC with the 1.1 genotype, but did not influence IL-12p40 production from PBMC with the 1.2/2.2 genotype. Cultures of PBMC with the 1.1 genotype produced significantly more IL-12p40 than PBMC with the 1.2/2.2 genotype after stimulation with PHA. Inhibition of p38 kinase upregulated p40 production only in cultures with the 1.1 genotype. Decreased IL-23 production was observed in C3bgp-stimulated cultures after the inhibition of p38 regardless of the genotype of the tested cells. We concluded that IL-12p40 and IL-23 expression, which is mediated by the p38 and JNK intracellular signaling pathways, is influenced by IL12Bpro polymorphism.

Immunoregulatory effects on T lymphocytes by human mesenchymal stromal cells isolated from bone marrow, amniotic fluid, and placenta

“…We observed a distinctly high concentration of IL-12 in MSCs, especially in BM-and PL-MSCs. Independent of their origin, MSCs also produced a moderate concentration of TNF-a and negligible amounts of IL-2 and IFN-g. PHA-PBMCs had high levels of Th1 cytokines, as just reported [23][24][25]. In all co-culture experiments, we observed decreases in all Th1 cytokines.…”

“…Phytohemagglutinin-stimulated PBMCs were used as the control and the range of analyzed cytokines was similar to those reported in literature [23][24][25]. MSCs constitutively produced: (i) negligible levels of Th1 cytokines, except IL-12, which was higher than IL-12 levels in PHA-PBMCs; (ii) very low levels of Th2 cytokines; and (iii) significant levels of IL-6 and IL-17.…”

Cytokine Gene Polymorphisms in Colorectal Cancer

“…The promoter polymorphisms in the human IL12B gene could influence JNK and p38 MAPKs control of IL-12p40 expression in human PBMC in response to mitogens and proinflammatory stimuli. The study of Dobreva et al, revealed that JNK and p38 MAPK inhibition in PBMC stimulated with C3bgp and LPS, significantly upregulated the IL-12p40 production from IL12Bpro-1 homozygotes and did not influence the IL-12p40 production from 1.2/2.2 genotypes (Dobreva et al, 2009). Also, the p38 inhibition led to significant increase of IL-12p40 production in IL12Bpro-1 homozygous PBMC stimulated with PHA.…”

“…Several polymorphisms have been described in the IL12B gene, encoding IL-12p40 subunit, including a single-nucleotide polymorphism in 3'-untranslated region (UTR) of IL12B with number rs3212227 and a complex polymorphism in promoter region of the IL12B (IL12Bpro), resulting from 4bp microinsertion combined with an AA/GC transition (rs17860508). Moreover, several studies have demonstrated that these two polymorphisms affect gene expression and IL-12 production (Morahan et al, 2001;Seegers et al, 2002;Muller-Berghaus et al, 2004;Stanilova and Miteva, 2005;Stanilova et al, 2008;Dobreva et al, 2009) and consequently could influence the pathogenesis of CRC. To test this hypothesis, we performed a case-control study to investigate the association between these gene polymorphisms and the risk of colorectal cancer.…”