Am. J. Respir. Cell Mol. Biol., Volume 27, Number 1, July, 2002 91-98

Silica-Induced Apoptosis in Murine Macrophage
Involvement of Tumor Necrosis Factor- and Nuclear Factor-B Activation

Evelyne Gozal, Luis A. Ortiz, Xiaoyan Zou, Matthew E. Burow, Joseph A. Lasky, and Mitchell Friedman

Section of Pulmonary Diseases, Critical Care, and Environmental Medicine, and the Lung Biology Program, Tulane-Xavier Center for Bioenvironmental Research, Tulane University Medical Center, New Orleans, Louisiana

Alveolar macrophages play a critical role in silica-induced lung fibrosis. Silica exposure induces tumor necrosis factor (TNF)- release and nuclear factor (NF)-B activation, and apoptotic mechanisms have been implicated in silica-induced pathogenesis. To characterize potential relationships between these signaling events, we studied their induction in two murine macrophage cell lines. The RAW 264.7 macrophage cell line was more sensitive, and the IC-21 macrophage cell line more tolerant to silica exposure (0.2 or 1 mg/ml for 6 h) as evidenced by significantly higher apoptotic responses in RAW 264.7 (P < 0.05). RAW 264.7 macrophages exhibited enhanced TNF- production and NF-B activation in response to silica, whereas IC-21 macrophages did not produce TNF- in response to silica and did not induce NF-B nuclear binding. Inhibition of NF-B in RAW 264.7 cells with BAY11-7082 significantly increased apoptosis while inhibiting TNF- release. In addition, TNF- and NF-B activation, but not apoptosis, were induced by lipopolysaccharide (LPS) in both cell lines, and NF-B inhibition reduced LPS-induced TNF- release. These data suggest that TNF- induction is dependent on NF-B activation in both cell lines. However, silica can induce apoptosis in murine macrophages, independently of TNF- stimulation, as in IC-21 macrophages. Furthermore, NF-B activation in macrophages may play dual roles, both pro- and antiapoptotic during silica injury.

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