Long-Lasting Production of TGF-β1 by Alveolar Macrophages Exposed to Low Doses of Asbestos without Apoptosis

Abstract

Alveolar macrophages (AMs) exposed to asbestos are well known to produce TNF-alpha, which induces the production of TGF-beta1, leading to lung fibrogenesis. The present study examines the production of TGF-beta1 by AMs exposed to chrysotile B asbestos (CH) in vivo or in vitro and the relationship between TGF-beta1 production and apoptosis in cultures of AMs. Rats instilled with CH via the trachea showed increases in TNF-alpha, IL-1beta and IL-6 in the bronchoalveolar lavage fluid (BALF) 1 day after the instillation, followed by increases in TGF-beta1 and apoptotic cells 5 days after. The AMs from these BALFs produced a significantly increased amount of TGF-beta1 in culture compared to those from the control rats. The addition of 2.5 mug/cm2 of CH augmented the production of TGF-beta1 by the AMs from the control to the same level as produced by the AMs from the CH-treated rats. The apoptosis of AMs was not induced at 2.5 microg/cm2 of CH, but was drastically induced at over 12.5 microg/cm2. In contrast, the production of TGF-beta1 by AMs peaked at around 2.5 microg/cm2 of CH, and it lasted for 11 days. In addition, Bcl-2 and Bcl-xL increased in the AMs surviving under the exposure to CH. Taken together, these results indicate that AMs can autonomously, without other pulmonary cells, acquire the lasting ability to produce TGF-beta1 independently of apoptosis under low exposure to CH. The AMs with the lasting production of TGF-beta1 may contribute not only to lung fibrosis but also to immune suppression.