Dobreva Zlatka Georgieva, Stanilova Spaska Angelova, Miteva Lyuba Dineva
Department of Molecular Biology, Immunology & Genetics, Faculty of Medicine, Trakia University, Stara Zagora, Bulgaria.
Cell Mol Biol Lett. 2009;14(4):609-21. doi: 10.2478/s11658-009-0022-4. Epub 2009 Jun 25.
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.
白细胞介素-12p40基因（IL12B）编码p40多肽链，该链与p19共同构成IL-23。据报道，位于转录起始位点-2703 bp处的双等位基因启动子多态性（IL12Bpro）与IL-12p40的产生有关。为了阐明IL-12p40和IL-23的产生对IL12Bpro多态性的依赖性，以及与丝裂原活化蛋白激酶（MAPK）信号转导途径的关系，我们检测了JNK和p38抑制对来自具有1.1和1.2/2.2 IL12Bpro基因型的健康供体的外周血单个核细胞（PBMC）经刺激后这些细胞因子分泌的影响。用脂多糖（LPS）和C3bgp刺激后，具有1.1和1.2/2.2基因型的PBMC产生的IL-12p40量大致相等。刺激前抑制JNK和p38可显著上调具有1.1基因型的PBMC产生的IL-12p40，但不影响具有1.2/2.2基因型的PBMC产生IL-12p40。用PHA刺激后，具有1.1基因型的PBMC产生的IL-12p40明显多于具有1.2/2.2基因型的PBMC。仅在具有1.1基因型的培养物中，抑制p38激酶可上调p40的产生。在抑制p38后，无论受试细胞的基因型如何，在C3bgp刺激的培养物中均观察到IL-23产生减少。我们得出结论，由p38和JNK细胞内信号通路介导的IL-12p40和IL-23表达受IL12Bpro多态性影响。
