TNF-alpha production by alveolar macrophages in mineral-dust-induced fibrosis.

Abstract

Macrophages are the predominant cell type in the chronic inflammatory reaction associated with the development of mineral-dust-induced fibrosis. Macrophages are potent producers of cytokines, which have recently emerged as potentially important mediators in regulating inflammatory states. I investigated cytokine production by alveolar macrophages (AM), with a special emphasis on tumor necrosis factor-$\alpha$, in experimental lung fibrosis induced by mineral dusts. Exposure to fibrigenic dusts had a bimodal effect on TNF-$\alpha$ production by AM. First, suppressed TNF-$\alpha$ production after 1 and 3 weeks of exposure. Second, after 6 weeks of exposure TNF-$\alpha$ production was high. By contrast, interleukin-1 (IL-1) and interleukin-6 (IL-6) production was increased in animals with inflammation with and without fibrosis. Potentiations in IL-1 and IL-6 production were associated with the early stage of the inflammatory reaction and were inversely correlated with TNF-$\alpha$ changes. Interestingly, alterations in TNF-$\alpha$ production were associated with definite shifts in the distribution size of AM suggesting that the overall production of TNF-$\alpha$ may be regulated by the specific class of AM present at sites of inflammation. To our knowledge, our study brings the first evidence for a negative modulation of TNF-$\alpha$ during inflammatory reactions leading to lung fibrosis. Furthermore, experiments with neutralizing antibody to TGF-$\beta$ suggest a role for TGF-$\beta$ in down-regulating TNF-$\alpha$ production in our system.