Role of the endogenous prostaglandin E-2 in human lung fibroblast interleukin-11 production

Interleukin-11 (IL-11) is known to be a member of the interleukin-6 (IL-6)- type cytokine family. IL-11 is likely to be a major determinant of immune r egulation in acute and chronic inflammatory lung diseases, although it is n ot directly linked with specific disease processes. It has already been sho wn that although unstimulated human lung fibroblasts did not produce signif icant amounts of IL-11, the addition of interleukin-1 alpha (IL-1 alpha) an d/or transforming growth factor-beta (TGF-beta) stimulated fibroblasts dose -dependently to produce IL-11. Northern blot analysis showed that these sti mulators also upregulated IL-11 mRNA expression. As it has been previously reported that IL-1 and TGF-beta stimulate prostaglandin E-2 (PGE(2)) releas e from lung fibroblasts, we investigate here the role of endogenous PGE(2) and the direct effects of the two inhibitors of prostaglandin synthesis, in domethacin and dexamethasone, on IL-11 production by human lung fibroblasts . The addition of indomethacin, a cyclo-oxygenase inhibitor, resulted in si gnificant suppression of IL-11 production and mRNA expression in lung fibro blasts. There was no detectable effect of PGE(2) alone on IL-11 levels; how ever, the suppression of IL-11 production by indomethacin was almost comple tely reversed by addition of PGE(2). In contrast, suppression of IL-11 prod uction by indomenthacin was not reversed by addition of thromboxane B-2 and carbocyclic thromboxane A(2) In addition, dexamethasone completely suppres sed IL-11 production and downregulated IL-11 mRNA. These results suggest th at endogenous PGE(2) acts as an autocrine stimulus for IL-11 production by human lung fibroblasts activated by IL-1 alpha and TCF-beta. (C) 1999 HARCO URT PUBLISHERS LTD.