ABSTRACT
Ishikawa, Tomomoto and Patricia L. Morris. 2006. "A multistep kinase-based Sertoli cell autocrine-amplifying loop regulates prostaglandins, their receptors, and cytokines," Endocrinology 147(4): 1706–1716.
In Sertoli epithelial cells, the interleukin (IL)-1β induces prostaglandins (PG) PGE2, PGF2α and cPGI2 (7-, 11-, and 2-fold, respectively), but not PGD2, production. Cyclohexamide pretreatment inhibiting protein synthesis prevents IL-1β increases in PG levels, indicating that induction requires de novo protein synthesis. IL-1β-regulated PGE2 and PGF2α production and cytokine expression require activation of cyclooxygenase-2 (COX-2) and cJun-N terminal kinase, as shown using specific enzyme inhibition. PGE2 and PGF2α stimulate expression of IL-1α, -1β, and -6, findings consistent with PG involvement in interleukin signaling within the seminiferous tubule. PGE2 and PGF2α reverse COX-2-mediated inhibition of IL-1β induction of cytokine expression and PG production. Sertoli prostaglandin receptor expression was determined; four known EP subtypes (1–4), and the FP and IP 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-1β 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 (PKA) inhibition blocks both IL-1β- and PGE2-induced cytokines. Together the data indicate an autocrine-amplifying loop involving IL-1β-regulated Sertoli function mediated by COX-2-induced PGE2 and PGF2α production. PGE2 activates EP2 and/or EP4 receptor(s) and the PKA-cAMP pathway; PGF2α activates FP receptor-PKC signaling. Further identification of the molecular mechanisms subserving these mediators may offer new insights into physiological events as well as pro-inflammatory-mediated pathogenesis in the testis.
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