Abstract
In testicular epithelial Sertoli cells (SC), IL-1β regulates estradiol and lactate production, transferrin secretion, and IL-6 expression; while each subsequently influences developing germ cells and spermatogenesis, little is known about the signalling mechanisms involved. In other specialized cell types, IL-1β potently induces reactive oxygen species (ROS) and/or cyclooxygenase-2 (COX-2). We review that IL-1β stimulates COX activity, mediating the expression of interleukins and steroidogenic acute regulatory (StAR)-related lipid transfer (START domain) proteins. IL-1β does not generate ROS but does rapidly phosphorylate cJun-NH2-terminal kinase (JNK), but not p44/42 or p38 mitogen-activated protein kinases. In atime- and dose-dependent manners, IL-1β significantly increases the levels of COX-2 mRNA and protein with concomitant increases in IL-1α, IL-6, and IL-1β mRNAs. Cyclohexamide (CHX) blocks increases in COX-2 protein. The intracellular StART domain levels are significantly altered consistent with posttranscriptional and posttranslational regulation. IL-1β rapidly decreases the levels of precursor and mature sterol regulatory element-binding protein-1 (SREBP-1), changes not affected by CHX, and suggesting coordinate regulation of StAR expression and cholesterol metabolism. Together these data demonstrate that COX-2 activity regulates SC cytokines and START domain lipid sensors. Also, IL-1β induces the production of prostaglandins (PG) PGE2 and PGF2α. IIL-1β-regulated PGE2 and PGF2α production, and cytokine expression require initial activation of cyclooxygenase-2 (COX-2) and JNK, as shown using specific enzyme inhibition. Sertoli cell PG receptor expression was determined; four known EP subtypes, and the FP and IP receptors were detected using RNA and protein analyses. IL-1β regulates both the EP2 mRNA and protein levels, the data being consistent with a regulatory feedback loop. 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 an 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-PKC signalling. Further identification of the molecular mechanisms subserving these mediators may offer new insights into the physiological events as well as pro-inflammatory mediated pathogenesis in the testis.
