Contribution of stress-activated MAP kinases to nivalenol-caused cytotoxicity and interleukin-8 secretion in HL60 cells

Abstract

To elucidate the molecular mechanism underlying the toxicity of the Fusarium mycotoxin nivalenol, we investigated the involvement of stress-activated MAP kinases (SAPKs; c-Jun Nterminal kinases (JNKs) and p38s) in nivalenol-caused cytotoxicity and interleukin (IL) -8 secretion in human promyelocytic leukemia HL60 cells. Nivalenol treatment for 24 h increased the phosphorylated (i.e., the active-form) JNKs with maximum effect at 1 μg/mL; when nivalenol was given at this concentration in a time-series experiment, phosphorylated JNK quantity peaked at 12 h and then decreased. Essentially the same results were obtained for phosphorylated (active-form) p38s. To elucidate the functions of SAPKs, we investigated the effects of the JNK-specific inhibitor SP600125 and the p38-specific inhibitor SB203580 on nivalenol-caused cytotoxicity and IL-8 secretion. Nivalenol hindered cell proliferation regardless of the presence or absence of SAPK-specific inhibitors. However, co-treatment with SAPK inhibitors reduced this effect, indicating that JNKs and p38s play roles in nivalenolassociated retardation of cell proliferation. SP600125 significantly reduced nivalenol-induced IL-8 secretion, indicating that JNKs contribute to this phenomenon. SB203580 moderately lessened nivalenol-elicited IL-8 secretion, however, the contribution of p38s to nivalenolinduced IL-8 secretion appears to be meaningful, because SB203580 alone markedly increased IL-8 secretion.