IL-1-BETA INHIBITS ET-1 PRODUCTION BY ATII CELLS IN-VITRO - EVIDENCE FOR INVOLVEMENT OF CYCLOOXYGENASE-2 PATHWAY

The aim of this study was to characterize the effect of alveolar macro phage (AM) secretory products on endothelin (ET)-1 production by rat a lveolar type II (ATII) cells in primary culture. We quantified preproe ndothelin (ppET)-1 mRNA by Northern blot and ET-1 concentrations in ce ll supernatants by enzyme-linked immunosorbent assay. Conditioned medi um (CM) from rat adherent AM decreased the ppET-1 mRNA levels in ATII cells and reduced ET-1 concentrations in cell culture supernatants. Th is effect was mediated by interleukin (IL)-1 beta as shown by pretreat ment of CM with an anti-IL-1 beta neutralizing antiserum. IL-1 beta ef fect was dependent on protein synthesis, was partially prevented with indomethacin, and was totally prevented with dexamethasone. Specific i nhibition ofcyclooxygenase 2 activity completely reversed the effect o f IL-1 beta. We conclude that rat AM inhibit ET-1 production by rat AT II cells in vitro through IL-1 beta secretion. The IL-1 beta-mediated inhibition is dependent on the cyclooxygenase 2 pathway. Downregulatio n of ET-1 production by activated AM could limit the intra-alveolar bu rden of this profibrogenic peptide and thus could prevent fibrosis dev elopment.