The proinflammatory cytokine TNF has important actions at the level of the ovary, among others inhibition of P450_AROM aromatase activity and the secretion of inhibin, two proteins that are markers of the granulosa cells differentiated status. Because the transcription of both P450_AROM and inhibin -subunit can be suppressed in the ovary by ICER, the inducible repressor isoform of CREM, we have investigated if TNF and its intracellular messenger ceramide can induce ICER expression and the mechanisms whereby the induction is accomplished. ICER mRNA levels were assessed by RT-PCR in granulosa cells treated with TNF, the ceramide mobilizing enzyme sphingomyelinase or C6-cer a cell permeant ceramide analog. Rapid (3 h) yet transient increases in the four isoforms of ICER were observed en response to all treatments. Likewise ICER protein measured by immunoprecipitation with a specific Ab increases after TNF, SMase or C6-cer treatment. The mandatory phosphorylation of CREB was also observed in response to TNF, SMase or C6-cer and shown to be prevented by the p44/42 MAPK specific inhibitor PD098059 but no other kinases blockers. Activation of p44/42 MAPK by the cytokine and its messenger was subsequently demonstrated as well as the inhibition of ICER expression by PD098059. Finally the blocking of p44/42 MAPK activation prevented TNF inhibition of FSH-dependent increases in P450_AROM and inhibin -subunit mRNA levels, thus indicating that p44/42 MAPK-mediated ICER expression may be accountable for the effects of TNF on the expression of both proteins.