After application of haptens on the skin, immature dendritic cells (DC), also named Langerhans cells (LC), migrate to the draining lymph node to sensitize naïve T-lymphocytes. Migration of DC involves many factors including the Cys-Cys chemokine receptor, CCR7. We investigated the effects of two well-known haptens, dinitrochlorobenzene (DNCB) and nickel (NiSO(4)), on the expression of CCR7 on human DC derived from CD34(+) progenitor cells. Both haptens were able to induce CCR7 expression and DC migration in response to Cys-Cys chemokine ligand, CCL19. Since interleukin (IL)-1beta and tumor necrosis factor (TNF)-alpha have been shown to participate in LC migration during contact hypersensitivity, we tested the effect of their neutralization on CCR7 expression. Neutralization of IL-1beta activity did not modify CCR7 expression in response to both haptens. CCR7 expression was strongly dependent on TNF-alpha in the case of DNCB, however, neutralization of TNF-alpha only partially reduced CCR7 expression upon NiSO(4) treatment. DNCB, NiSO(4) and TNF-alpha activated p38 mitogen-activated protein kinases (MAPK) and c-jun N-terminal kinase (JNK). Both p38 MAPK and JNK participated to TNF-alpha production induced by DNCB. Inhibition of both p38 MAPK and JNK affected significantly CCR7 expression upon nickel treatment whereas only inhibition of p38 MAPK but not of JNK downregulated CCR7 in the case of TNF-alpha stimulation. These results suggest that MAPK are necessary for haptens to induce CCR7 expression. NiSO(4), however, activates directly CCR7 expression through p38 MAPK and JNK activation whereas DNCB needs TNF-alpha whose secretion is also regulated by p38 MAPK and JNK.

Dendritic cell (DC) activation is a critical event for the induction of an immune response to haptens. Although signaling pathways such as mitogen-activated protein kinase (MAPK) family members have been reported to play a role in DC activation by haptens, little is known about the implication of the nuclear factor kappa B (NF-kappaB) pathway. In this work, we showed that NiSO(4) induced the expression of HLA-DR, CD83, CD86, and CD40 and the production of interleukin (IL)-8, IL-6, and IL-12p40 in human DCs, whereas DNCB induced mainly the expression of CD83 and CD86 and the production of IL-8. NiSO(4) but not DNCB was able to activate the degradation of IkappaB-alpha leading to the binding of the p65 subunit of NF-kappaB on specific DNA probes. Inhibition of the NF-kappaB pathway using BAY 11-7085 prevents both CD40 and HLA-DR expression and cytokine production induced by NiSO(4). However, BAY 11-7085 only partially inhibited CD86 and CD83 expression induced by NiSO(4). In addition, p38 MAPK and NF-kappaB were independently activated by NiSO(4) since SB203580 did not inhibit NF-kappaB activation by NiSO(4). Interestingly, we also showed that DNCB inhibited the degradation of IkappaB-alpha induced by tumor necrosis factor-alpha leading to alteration of CD40, HLA-DR, and CD83 expression but not of CD86 and CCR7. Extensive modifications of DC phenotype by NiSO(4) in comparison to DNCB are probably the consequence of NF-kappaB activation by NiSO(4) but not by DNCB.