REGULATION OF PROSTAGLANDIN ENDOPEROXIDE SYNTHASE GENE-EXPRESSION IN RAT MESANGIAL CELLS BY INTERLEUKIN-1-BETA

In primary cultures of rat mesangial cells from passage 3 to 6, interl eukin-1 beta (IL-1) induced a time-dependent increase in prostaglandin E(2) (PGE(2)) formation and release into the extracellular medium. Th is increase was associated with a dramatic upregulation of the steady- state levels of mRNA for the prostaglandin endoperoxide synthase (PES) -2 gene transcript as demonstrated by Northern analysis. In contrast, there did not appear to be a significant increase in the mRNA levels f or a 2.8-kb transcript for the PES-1 gene. At 18 h of exposure to IL-1 , the steady-state level of message for PES-2 remained elevated at 50% of the 2-h time point. Culturing the cells in the presence of cyclohe ximide and IL-1 demonstrated a superinduction of the PES-2 message wit hout any change in PES-1 message. The tumor-promoting phorbol ester, p horbol myristate acetate (PMA), was also associated with an upregulati on of the message for the PES-2 gene and did not influence the levels of the message for the PES-1 gene as demonstrated by Northern analysis . Dexamethasone (Dex) inhibited to control levels the induction by PMA , but the induction of the message by IL-1 was only inhibited 30%. Des pite 70% of the message being present by 2 h of induction, Dex was cap able of totally inhibiting the inductive effect of IL-1 with respect t o PGE(2) biosynthesis. Immunocytochemical studies demonstrated a drama tic induction of PES-2 protein by IL-1, which was inhibited by Dex. Th e data suggest that Dex inhibits the translation of the PES-2 protein.