TENASCIN-C EXPRESSION IN HUMAN EPIDERMAL-KERATINOCYTES IS REGULATED BY INFLAMMATORY CYTOKINES AND A STRESS-RESPONSE PATHWAY

Recently we showed that human epidermal keratinocytes express the extr acellular matrix protein tenascin-C (TN-C) during wound healing, but n ot in normal adult skin. To gain further insight into the regulation o f epidermal TN-C expression, we tested the effect of various stimuli o n TN-C expression by cultured keratinocytes. Our results indicate that IL-4 is a very strong inducer of TN-C protein and mRNA expression in normal keratinocytes. Furthermore, TNF alpha and IFN gamma moderately increased TN-C expression. No other cytokines and growth factors that we tested, including various factors that stimulate TN-C expression in mesenchymal cells, significantly affected TN-C secretion by cultured keratinocytes. The regulation of TN-C expression in keratinocytes is d istinct from that of fibronectin, since IL-4 and IFN gamma did not aff ect fibronectin expression in our experiments, and TNF alpha only slig htly increased fibronectin levels. To investigate the role of cellular stress response pathways that can be activated by TNF alpha in the re gulation of TN-C expression, we tested the effect of different inhibit ors and an activator of these intracellular signalling cascades. The r esults show that the p38 MAP-kinase pathway is not involved in TNF alp ha-induced TN-C expression in cultured keratinocytes. Activation of th e JNK/SAPK-1 pathway by the addition of sphingomyelinase resulted in a dose-dependent increase of TN-C expression. TN-C expression by squamo us carcinoma cell lines was differentially affected by the cytokines t hat stimulated TN-C expression in normal keratinocytes: TNF alpha agai n increased TN-C secretion, but IL-4 and IFN gamma had little effect. We conclude that there are distinct regulation mechanisms for TN-C exp ression in normal keratinocytes, tumor-derived keratinocytes and mesen chymal cells. The observation that TN-C is abundant in inflamed skin i s a strong indication that inflammatory cytokines such as IL-4, TNF al pha and IFN gamma could also be involved in the regulation of epiderma l TN-C expression in vivo.