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A Multistep Kinase-Based Sertoli Cell Autocrine-Amplifying Loop Regulates Prostaglandins, Their Receptors, and Cytokines

Center for Biomedical Research, Population Council (T.I., P.L.M.) and The Rockefeller University (P.L.M.), New York, New York 10021

Address all correspondence and requests for reprints to: Dr. Patricia L. Morris, Center for Biomedical Research, Population Council and The Rockefeller University, 1230 York Avenue, New York, New York 10021. E-mail: p-morris{at}popcbr.rockefeller.edu.

In Sertoli epithelial cells, the IL-1ß induces prostaglandins (PG) PGE₂, PGF₂ and PGI₂ (7-, 11-, and 2-fold, respectively), but not PGD₂, production. Cyclohexamide pretreatment inhibiting protein synthesis prevents IL-1ß increases in PG levels, indicating that induction requires de novo protein synthesis. IL-1ß-regulated PGE₂ and PGF₂ production and cytokine expression require activation of cyclooxygenase-2 (COX-2) and c-Jun NH₂-terminal kinase, as shown using specific enzyme inhibition. PGE₂ and PGF₂ stimulate expression of IL-1, -1ß, and -6, findings consistent with PG involvement in IL signaling within the seminiferous tubule. PGE₂ and PGF₂ reverse COX-2-mediated inhibition of IL-1ß induction of cytokine expression and PG production. Sertoli PG receptor expression was determined; four known E-prostanoid receptor (EP) subtypes (1–4) and the F-prostanoid and prostacyclin prostanoid receptors were demonstrated using RNA and protein analyses. Pharmacological characterization of Sertoli PG receptors associated with cytokine regulation was ascertained by quantitative real-time RT-PCR analyses. IL-1ß regulates both EP₂ mRNA and protein levels, data consistent with a regulatory feedback loop. Butaprost (EP₂ agonist) and 11-deoxy PGE₁ (EP₂ and EP₄ agonist) treatments show that EP₂ receptor activation stimulates Sertoli cytokine expression. Consistent with EP₂-cAMP signaling, protein kinase A inhibition blocks both IL-1ß- and PGE₂-induced cytokines. Together, the data indicate an autocrine-amplifying loop involving IL-1ß-regulated Sertoli function mediated by COX-2-induced PGE₂ and PGF₂ production. PGE₂ activates EP₂ and/or EP₄ receptor(s) and the protein kinase A-cAMP pathway; PGF₂ activates F-prostanoid receptor-protein kinase C signaling. Further identification of the molecular mechanisms subserving these mediators may offer new insights into physiological events as well as proinflammatory-mediated pathogenesis in the testis.

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