Role of transforming growth factor-β1in down-regulating TNF production by alveolar macrophages during asbestos-induced pulmonary fibrosis

Irma Lemaire,Sophie Ouellet

doi:10.1155/s0962935196000063

Abstract

Activation of alveolar macrophages (AM) for tumour necrosis factor production is suppressed initially during the inflammatory response to fibrogenic dusts. We investigated the mechanisms involved in TNF suppression, notably the role of other AM-derived mediators including prostaglandin E2 (PGE2), transforming growth factor-β1 (TGF-β1), and interleukin 6 (IL-6). The action of PGE2 and TGF-β1, on AM was different. At physiologically relevant doses (25–300 pg/ml), PGE2 did not cause significant inhibition of Hpopolysaccharide (Lps)-induced TNF release by AM in vitro but stimulated IL-6 (up to six fold), an inhibitor of AM-derived TNT. In contrast, TGF-β1 (0.5–50 ng/ml) inhibited both LPS-induced TNT and IL-6 release by 50% but had no effect on PGE2 production by AM. To determine the respective contribution of these different inhibitors in TNF suppression, AM from rats exposed to fibrogenic asbestos for weeks were treated with neutralizing antibody against TGF-β1 or indomethacin, an inhibitor of PGE2 synthesis. Treatment of rat AM with anti-TGF-β1 but not indomethacin, abrogated the observed TNT suppression. These results suggest that an autocrine, TGF-β1-dependent mechanism is involved in the down-regulation of TNF production by rat AM from animals with lung fibrosis.

Highlights

Alveolar macrophages (AM) are an important source of numerous cytokines and are a primary cell type in chronic inflammatory reactions induced by fibrogenic dusts.[2]
These results suggest that tumour necrosis factor-or (TNF) response in AM from animals with lung fibrosis is inhibited in an autocrine fashion by TGF
Prostaglandin E2 (PGE2) inhibited LPS-induced TNF release from AM by 50% in a dose-dependent manner with half-maximal effect observed at 25 Ig/ml (Fig. 1A)

Summary

Introduction

Alveolar macrophages (AM) are an important source of numerous cytokines and are a primary cell type in chronic inflammatory reactions induced by fibrogenic dusts.[2] It is likely that the contribution of AM-derived cytokines plays an important role in the maintenance and progression of pulmonary inflammation. TNF is frequently found at sites of inflammatory reactions and higher levels of TNF messenger RNA were identified in lung tissue of mice treated with silica[5] and bleomycin.[6] With regard to basal and LPS-stimulated TNF production by AM, variable responses including stimulation as well as inhibition or no change have been reported in experimental silicosis.7-I0 Less information is available concerning the contribution of AM-derived TNF in asbestos-induced fibrosis. We reported bidirectional changes in LPS-stimulated TNF production by rat (C) 1996 Rapid Science Publishers

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Conclusion