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Induction of Interleukin-6 Release by Interleukin-1 in Rat Anterior Pituitary Cells in Vitro: Evidence for an Eicosanoid-Dependent Mechanism^*

Departments of Medicine and Neuroscience, and the Center for Cancer Research, University of Virginia Health Sciences Center Charlottesville, Virginia 22908

Address requests for reprints to: Dr. Bryan L. Spangelo, Department of Physiology, Medical University of South Carolina, 171 Ashley Avenue, Charleston, South Carolina 29425β2258.

Abstract

We have reported previously that a subpopulation(s) of anterior pituitary cells released IL-6 and that this release was stimulated by interleukin-1 (IL-1) through a noncAMP- dependent mechanism. We now report that IL-1 induces IL-6 release from anterior pituitary cells in an eicosanoid-dependent manner. Dispersed rat anterior pituitary cells were briefly prelabeled (2β3 h) with [³H]arachidonic acid (AA) to esterify the fatty acid within the lipid pool. Incubation of these prelabeled cells with 25 ng/ml IL-β caused an increase only within 1β2 min in the amount of free [³H]AA detected in the extracts of the cells. During 15- to 30-min incubations, IL-1β (25 ng/ml) caused an increased accumulation of [³H]AA in the incubation medium which reached levels similar to those induced by 100 nM TRH. Perifused anterior pituitary cells responded to IL-1β (25 ng/ml) with a rapid (<2 min), biphasic, and reversible efflux of [³H]AA. The [³H]AA appears to have been derived from choline phospholipids, as formation of [³H]glycerophosphorylcholine was substantially increased by exposure of [³H] choline-prelabeled cells to either IL-1 (171%) or IL-1β (236%); in addition, the complete deacylation of phosphatidylcholine suggests that other fatty acid species are liberated as a consequence of IL-1 receptor activation and, thus, may also contribute to the actions of IL-1 and IL-1β. However, the levels of [³H] phosphorylcholine and [³H]choline were unchanged as well as those of catabolites of other lipid species. These data suggested an involvement of phospholipase-A₂ (PLA₂) in mediating the IL-1 induction of IL-6 release. Subsequently, we used inhibitors of the PLA₂, cyclooxygenase, and lipoxygenase enzymes to investigate a possible role for the generation of AA and its subsequent enzymatc conversion in the signal transduction pathway activated by IL-1. The PLA₂ inhibitor aristolochic acid (10 µM) blocked IL-1β-induced IL-6 release and the release of IL-6 caused by Pyrularia pubera thionin (5 µg/ml), a stimulator of PLA₂ activity. The cyclooxygenase inhibitor indomethacin (10 nM) did not inhibit IL-1β-induced IL-6 release. In contrast, the general lipoxygenase inhibitor nordihydroguaiaretic acid (10 µM) and the more specific 5-lipoxygenase inhibitors AA861 and RHC5901 (both 10 µM) reduced basal and blocked IL-β-induced IL-6-release. Ethacrynic acid, an inhibitor of leukotriene C₄ synthesis, also reduced basal and IL-1β-induced IL-6 release. Vasoactive intestinal peptide-, prostaglandin E₂-, and lipopolysaccharide- induced IL-6 release were similarly affected by these PLA₂, cyclooxygenase, and lipoxygenase inhibitors. These results suggest that at least with respect to amine-linked phospholipids, an apparent increase in the combined activities of PLAi and PLA₂, but not of PLC or PLD, accompanies activation of the IL-1 receptor in anterior pituitary cells. In addition, the generation of AA and/or metabolites of the lipoxygenase pathway appears to be involved in the signal transduction pathway activated by IL-1 in the anterior pituitary. (Endocrinology 129: 2886-2894,1991)

Footnotes

^* This work was supported by grants from the NIDDK (DK-42059; to B.L.S.) and the NCI (CA-07535; to R.M.M.).

Received June 5, 1991.

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