Metallic haptens induce differential phenotype of human dendritic cells through activation of mitogen-activated protein kinase and NF-kappaB pathways.

Dendritic cells (DCs) play a major role in the regulation of immune responses to a variety of antigens (Ag) and haptens which participate in the process of DC maturation. Indeed, metallic haptens are able to induce DC maturation in vitro but the mechanism of this maturation is not well understood. We and others have already shown that NiSO(4) activates p38 mitogen-activated protein kinases (p38MAPK), c-jun N-terminal kinase (JNK), extracellular signal-regulated kinase (ERK) and the transcription factor NF-kappaB during the early events of DCs maturation. However, the effect of other metallic haptens on DC maturation is still poorly understood. In the present study, using dendritic cells derived from CD34(+) cord blood cells, we showed that both NiSO(4) and CoCl(2) induced the expression of CD86, CD83, HLA-DR and CD40 and the production of IL-6 in human DCs while K(2)Cr(2)O(7) induced only a slight upregulation of CD86. Interestingly, only NiSO(4) was able to induce the production of IL-12p40. NiSO(4) and CoCl(2) but not K(2)Cr(2)O(7) were able to activate the MAPK pathway and the transcription factor NF-kappaB. The role of MAPKs in metals-induced DC maturation was then evaluated using well-described pharmacological inhibitors. Our results suggest that p38MAPK activation regulates the expression of CD86 and CD83 induced by NiSO(4) while it only affects the expression of CD83 induced by CoCl(2). IL-6 production induced by NiSO(4) and CoCl(2) strongly depended on all MAPKs. IL-12p40 synthesis after NiSO(4) treatment was regulated by both p38MAPK and JNK pathways whereas ERK may play an inhibitory role. Our results show that both NiSO(4) and CoCl(2) activate similar signaling pathways that are playing different roles in DC maturation depending on the hapten used.