Cyclooxygenase 2 Pathway Mediates IL-1β Regulation of IL-1α, -1β, and IL-6 mRNA Levels in Leydig Cell Progenitors

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Abstract
Prostanoids are arachidonic acid (AA) metabolites derived from the cyclooxygenase (COX1 and COX2 isozymes) pathway and are involved in signal transduction pathways activated by distinct ILs. Although COX1 is the constitutive isoform of COX, IL-1beta is a potent inducer of COX2 expression in distinct cell types. This study was designed to determine whether cyclooxygenases could mediate endogenous cytokine regulation in rat progenitor Leydig cells. COX and IL (IL-1alpha, IL-1beta, and IL-6) mRNAs were measured by PCR and real-time PCR analyses, respectively. COX function was assessed using COX activity inhibitors: indomethacin (INDO; COX1 and COX2 inhibitor) and NS-398 (COX2 selective inhibitor). Our data indicate that endogenous progenitor COX1 mRNA levels are low and are not regulated by IL-1beta. In contrast, COX2 mRNA is induced by IL-1beta at 6, 9, and 24 h. IL-1beta induction of IL mRNAs was in part significantly impaired in the presence of INDO or NS-398. Among the prostanoids tested, prostaglandin E(2) (PGE(2)), PGF(2alpha), and carbaprostacyclin reversed the INDO inhibition of IL production. PGs alone have no (IL-1alpha and IL-1beta) or a modest (IL-6) effect on IL mRNA levels. PGE(2), PGF(2alpha), and PGI(2) measurements show that IL-1beta treatment significantly increases progenitor Leydig cell production of these PGs. Taken together, our data demonstrate that this COX2 cascade is a regulator of cytokines in Leydig progenitors.

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