Silica-induced apoptosis in murine macrophage -: Involvement of tumor necrosis factor-α and nuclear factor-κB activation

Alveolar macrophages play a critical role in silica-induced lung fibrosis. Silica exposure induces tumor necrosis factor (TNF)-alpha release and nuclear factor (NF)-kappaB 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-alpha production and NF-kappa B activation in response to silica, whereas IC-21 macrophages did not produce TNF-alpha in response to silica and did not induce NF-kappa B nuclear binding. Inhibition of NF-kappa B in RAW 264.7 cells with BAY11-7082 significantly increased apoptosis while inhibiting TNF-alpha release. In addition, TNF-alpha and NF-kappa B activation, but not apoptosis, were induced by lipopolysaccharide (LPS) in both cell lines, and NF-kappa B inhibition reduced LPS-induced TNF-alpha release. These data suggest that TNF-alpha induction is dependent on NF-kappa B activation in both cell lines. However, silica can induce apoptosis in murine macrophages, independently of TNF-alpha stimulation, as in IC-21 macrophages. Furthermore, NF-kappa B activation in macrophages may play dual roles, both pro- and antiapoptotic during silica injury.