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Tumor Necrosis Factor- Activates Transcription of Inducible Repressor Form of 3',5'-Cyclic Adenosine 5'-Monophosphate-Responsive Element Binding Modulator and Represses P450 Aromatase and Inhibin -Subunit Expression in Rat Ovarian Granulosa Cells by a p44/42 Mitogen-Activated Protein Kinase-Dependent Mechanism

Departamento de Bioquímica y Fisiología, Facultad de Medicina, Universidad de Las Palmas de Gran Canaria, Las Palmas de Gran Canaria 35016, Spain

Address all correspondence and requests for reprints to: Luisa F. Fanjul, Department of Biochemistry and Physiology, Facultad de Medicina, Universidad de Las Palmas de Gran Canaria, Las Palmas de Gran Canaria, 35016, Spain. E-mail: lfanjul{at}dbbf.ulpgc.es.

The proinflammatory cytokine TNF has important actions at the level of the ovary, including inhibition of P450 aromatase (P450_AROM) activity and the secretion of inhibin, two proteins that are markers of the granulosa cell’s differentiated status. Because the transcription of both P450_AROM and inhibin -subunit can be suppressed in the ovary by the inducible repressor isoform of cAMP-responsive element binding modulator (ICER), we have investigated whether 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 (SMase), or C6-cer, a cell-permeant ceramide analog. Rapid (3 h) yet transient increases in the four isoforms of ICER were observed in response to all treatments. Likewise, ICER protein measured by immunoprecipitation with a specific antibody increases after TNF, SMase, or C6-cer treatment. The mandatory phosphorylation of cAMP-responsive element binding 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 kinase 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.