Mechanisms of IL-12 synthesis by human dendritic cells treated with the chemical sensitizer NiSO4.
Allergic contact dermatitis, caused by metallic ions, is a T cell-mediated inflammatory skin disease. IL-12 is a 70-kDa heterodimeric protein composed of IL-12p40 and IL-12p35, playing a major role in the generation of allergen-specific T cell responses. Dendritic cells (DCs) are APCs involved in the induction of primary immune responses, as they possess the ability to stimulate naive T cells. In this study, we address the question whether the sensitizer nickel sulfate (NiSO(4)) itself or in synergy with other signals can induce the secretion of IL-12p70 in human monocyte-derived DCs (Mo-DCs). We found that IL-12p40 was produced by Mo-DC in response to NiSO(4) stimulation. Addition of IFN-gamma concomitantly to NiSO(4) leads to IL-12p70 synthesis. NiSO(4) treatment leads to the activation of MAPK, NF-kappaB pathways, and IFN regulatory factor 1 (IRF-1). We investigated the role of these signaling pathways in IL-12 production using known pharmacological inhibitors of MAPK and NF-kappaB pathways and RNA interference-mediated silencing of IRF-1. Our results showed that p38 MAPK, NF-kappaB, and IRF-1 were involved in IL-12p40 production induced by NiSO(4). Moreover, IRF-1 silencing nearly totally abrogated IL-12p40 and IL-12p70 production provoked by NiSO(4) and IFN-gamma. In response to NiSO(4), we observed that STAT-1 was phosphorylated on both serine and tyrosine residues and participated to NiSO(4)-induced IRF-1 activation. N-acetylcysteine abolished STAT-1 phosphorylation, suggesting that STAT-1 activation may be dependent on NiSO(4)-induced alteration of the redox status of the cell. These results indicate that p38 MAPK, NF-kappaB, and IRF-1 are activated by NiSO(4) in Mo-DC and cooperate for IL-12 production.
Antonios
Diane
D
Universud, Institut National de la Santé et de la Recherche Médicale Unité Mixte de Recherche S 749 and 996, Faculté de Pharmacie, Châtenay-Malabry, France.
Rousseau
Philippe
P
Larangé
Alexandre
A
Kerdine-Römer
Saadia
S
Pallardy
Marc
M
D002478:Cells, Cultured; D003713:Dendritic Cells / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism*; D006801:Humans; D050856:Interferon Regulatory Factor-1 / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology; D007371:Interferon-gamma / Q000502:physiology; D007375:Interleukin-1 / Q000096:biosynthesis*; D018664:Interleukin-12 / Q000096:biosynthesis / Q000378:metabolism; D053765:Interleukin-12 Subunit p35 / Q000096:biosynthesis / Q000235:genetics; D053762:Interleukin-12 Subunit p40 / Q000096:biosynthesis; D007509:Irritants / Q000633:toxicity*; D048031:JNK Mitogen-Activated Protein Kinases / Q000502:physiology; D020935:MAP Kinase Signaling System / Q000276:immunology; D009000:Monocytes / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology; D009532:Nickel / Q000633:toxicity*; D012333:RNA, Messenger / Q000096:biosynthesis; D050794:STAT1 Transcription Factor / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology
C508858:IL12A protein, human; D050856:Interferon Regulatory Factor-1; D007375:Interleukin-1; D053765:Interleukin-12 Subunit p35; D053762:Interleukin-12 Subunit p40; D007509:Irritants; D016328:NF-kappa B; D012333:RNA, Messenger; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D018664:Interleukin-12; C029938:nickel sulfate; D009532:Nickel; D007371:Interferon-gamma; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases