Stress-activated protein kinase Jun N-terminal kinase is required for interleukin (IL)-1-induced IL-6 and IL-8 gene expression in the human epidermal carcinoma cell line KB

The cytokine interleukin-l (IL-1) is a major inflammatory hormone which activates a broad range of genes during inflammation. The signaling mechanisms triggered by IL-1 include activation of several distinct protein kinase systems. The stress-activated protein kinase (SAPK), also termed Jun N-terminal kinase (JNK), is activated particularly strongly by the cytokine. In an attempt to delineate its role in activation of gene expression by IL-1, we inhibited the IL-l-induced SAPK/JNK activity by stable overexpression of either a catalytically inactive mutant of SAPK beta (SAPK beta(K-R)) or antisense RNA to SAPK beta in human epidermal carcinoma cells. A detailed analysis of signal transduction in those cells showed that activation of neither NF kappa B nor p38 mitogen-activated protein kinase was affected, suggesting that we achieved specific blockade of the SAPK/JNK. In untransfected and vector-transfected KB cells, IL-1 induced a strong increase in expression of IL-6 and IL-8 mRNA, along with the synthesis of high amounts of the proteins. In two KB cell clones stably overexpressing the mutant SAPK beta(K-R), and three clones stably overexpressing antisense RNA to SAPK beta, expression of IL-6 and IL-8 in response to IL-1 was strongly reduced at both the mRNA and protein level. These data indicate that the SAPK/JNK pathway provides an indispensable signal for IL-l-induced expression of IL-6 and IL-8.