ROLE OF TRANSFORMING GROWTH FACTOR-BETA(1) IN DOWN-REGULATING TNF PRODUCTION BY ALVEOLAR MACROPHAGES DURING ASBESTOS-INDUCED PULMONARY FIBROSIS

Activation of alveolar macrophages (AM) for tumour necrosis factor (TN F) production is suppressed initially during the inflammatory response to fibrogenic dusts. We investigated the mechanisms involved in TNF s uppression, notably the role of other AM-derived mediators including p rostaglandin E(2) (PGE(2)), transforming growth factor-beta(1) (TGF-be ta(1)), and interleukin 6 (IL-6). The action of PGE(2) and TGF-beta(1) , on AM was different. At physiologically relevant doses (25-300 pg/ml ), PGE(2) did not cause significant inhibition of lipopolysaccharide ( LPS)-induced TNF release by AM in vitro but stimulated IL-6 (up to six fold), an inhibitor of AM-derived TNF. In contrast, TGF-beta(1) (0.5- 50 ng/ml) inhibited both LPS-induced TNF and IL-6 release by 50% but h ad no effect on PGE(2) production by AM. To determine the respective c ontribution of these different inhibitors in TNF suppression, AM from rats exposed to fibrogenic asbestos for 3 weeks were treated with neut ralizing antibody against TGF-beta(1) or indomethacin, abrogated the o bserved TNF suppression. These results suggest that an autocrine, TGF- beta(1)-dependent mechanism is involved in the down-regulation of TNF production by rat AM from animals with lung fibrosis.