MULTIPLE SECOND MESSENGER PATHWAYS REGULATE IL-1-BETA-INDUCED EXPRESSION OF PGHS-2 MESSENGER-RNA IN NORMAL HUMAN SKIN FIBROBLASTS

Very little is known about the specific regulation of PGHS-2 mRNA comp ared with PGHS-1 mRNA. Using normal human fibroblasts, we show that at baseline there is constitutive expression of PGHS-1 mRNA and barely d etectable amounts of PGHS-2 mRNA. There was a marked increase in PGHS- 2 mRNA transcription following exposure to IL-1 beta. Maximal expressi on of PCHS-2 mRNA occurred with concentrations of IL-1 beta greater th an or equal to 1 ng/ml at 3 hours after stimulation. Downregulation of protein kinase C (PKC) activity by pretreating fibroblast cultures wi th PMA inhibited IL-1-induced PGHS-2 mRNA expression without affecting the constitutive expression of PGHS-1 mRNA. The addition of various P KC inhibitors also blocked the IL-1 beta induction of PCHS-2 mRNA but did not alter PGHS-1 mRNA expression; inhibitors of protein kinase A ( PKA) or tyrosine kinase (TK) had only a limited effect on IL-1 beta-in duced PCHS-2 mRNA expression. These findings show that IL-1 beta incre ases PGHS-2 mRNA, at least in part, via activation of PKC. Activation of PKA or TK appears to have a more limited role in this process. (C) 1995 Wiley-Liss, Inc.