p38 Mitogen-activated protein kinase and extracellular signal-regulated kinases play distinct roles in the activation of dendritic cells by two representative haptens, NiCl₂ and 2,4-dinitrochlorobenzene

Previous studies have demonstrated that haptens induce several phenotypic and functional changes of dendritic cells in vivo as well as in vitro. Although recently, the crucial role of p38 mitogen-activated protein kinase has been reported in the activation of dendritic cells by haptens, the signal transduction elements involved in each phenotypic and functional changes that occur in the activation of dendritic cells by haptens remain unknown. Therefore, we examined the role of mitogen-activated protein kinases and nuclear factor-κB in the signal transduction of dendritic cells stimulated with two representative haptens, i.e., NiCl₂ and 2,4-dinitrochlorobenzene. Human monocyte-derived dendritic cells stimulated with 2,4-dinitrochlorobenzene induced the phosphorylation of p38 and stress-activated protein kinase/c-jun N-terminal kinases, whereas NiCl₂ induced that of p44/42 extracellular signal-regulated kinases, p38, and stress-activated protein kinase/c-jun N-terminal kinases. In addition, NiCl₂ phosphorylated inhibitor κB and activated nuclear factor-κB. In contrast, primary irritants, e.g., benzalkonium chloride, or sodium lauryl sulfate, did not activate these signal transduction pathways. By using specific inhibitors for extracellular signal-regulated kinases and p38 pathways, PD98059 and SB203580, respectively, we demonstrated that the augmentation of CD86, HLA-DR, and CD83, and the production of interleukin-8 along with its increased mRNA expression by monocyte-derived dendritic cells stimulated with 2,4-dinitrochlorobenzene, and the augmentation of CD83 and the interleukin-12 p40 production by monocyte-derived dendritic cells stimulated with NiCl₂, were suppressed by SB203580, whereas PD98059 suppressed the production of interleukin-1β and tumor necrosis factor-α, together with their increased mRNA expression by monocyte-derived dendritic cells treated with NiCl₂. On the other hand, in spite of the activation of nuclear factor-κB by monocyte-derived dendritic cells stimulated with NiCl₂, nuclear factor-κB inhibitor did not significantly affect the phenotypic and functional changes in the activation of monocyte-derived dendritic cells. These data indicate that NiCl₂ and 2,4-dinitrochlorobenzene stimulate different signal transduction pathways in monocyte-derived dendritic cells, and subsequently induce different phenotypic and functional changes in them.