Antiproliferative effect of IL-1 is mediated by p38 mitogen-activated protein kinase in human melanoma cell A375

The role of p38 mitogen-activated protein kinase (MAPK) in IL-1-induced gro wth inhibition was investigated using IL-1-sensitive human melanoma A375-C2 -1 cells and IL-1-resistant A375-R8 cells. In both cells, p38 MAPK was acti vated by IL-1, A selective inhibitor for p38 MAPK, SB203580, almost complet ely recovered the IL-1-induced growth inhibition in A375-C2-1 cells, IL-1-i nduced IL-6 production was also suppressed by SB203580, However,:the revers al effect of SB203580 was not due to the suppression of IL-6 production bec ause the SB203580 effect vas still observed in the presence of exogenous IL -6. Down-regulation of ornithine decarboxylase.(ODC) activity as well as it s protein level has been shown to be:essential for IL-1-induced growth inhi bition. SB203580 also reversed the IL-1-induced down-regulation of ODC acti vity and intracellular polyamine levels without affecting ODC mRNA levels i n A375-C2-1 cells. In IL-1-resistant R8 cells, however, IL-1 only slightly suppressed ODC activity. In A375-C2-1 cells, the mRNA expression level of a ntizyme (AZ), a regulatory factor of ODC activity, has been shown to be up- regulated by IL-1. IL-1-induced up-regulation of AZ mRNA level was not affe cted by SB203580. These findings demonstrate that p38 MAPK plays an importa nt role in IL-1-induced growth inhibition in A375 cells through down-regula ting ODC activity without affecting the level of ODC mRNA and AZ,mRNA, In I L-1-resistant A375-R8 cells, IL-1 signaling pathway is deficient between p3 8 MAPK activation and down-regulation of ODC activity.