Caspases downregulate nickel and hydrogen peroxide-induced IL-8 production via modification of c-Jun N-terminal...

Nickel (Ni) is a typical hapten in allergic contact dermatitis. However, it has been used in various metal materials due to its usefulness. Although Ni ions induce apoptosis of inflammatory cells and the expression of inflammatory cytokines such as interleukin-8 (IL-8), the effects of the apoptotic pathway on the signaling that induces cytokine production have not been sufficiently clarified. Here, we found that NiCl₂-induced IL-8 production was enhanced by the pan-caspase inhibitor Z-VAD-FMK in THP-1 cells. Moreover, Z-VAD-FMK enhanced H₂O₂-induced and NiCl₂-induced IL-8 production, but not TNF-α-induced one. The analyses of signaling pathways apparently showed that NiCl₂- and H₂O₂-induced phosphorylation of c-Jun, but not TNF-α-induced one were enhanced by Z-VAD-FMK. The cleavages of p54c-Jun N-terminal kinase (JNK) as well as PARP was induced by NiCl₂ and H₂O₂ but not by TNF-α. Finally, a JNK inhibitor, SP600125, inhibited Z-VAD-FMK-induced enhancement of IL-8 production. In summary, we showed that caspase activation in the apoptotic pathway actively downregulates the JNK-mediated activation of inflammatory cells. This study highlighted the significance of apoptosis in inflammatory diseases, including Ni-induced dermatitis.