Tumor necrosis factor receptor deficiency alters matrix metalloproteinase 13 tissue inhibitor of metalloproteinase 1 expression in murine silicosis

Murine exposure to silica is associated with enhanced tumor necrosis factor alpha (TNF-alpha) expression and matrix deposition. The regulation of TNF is mediated through TNF receptor (TNFR) activation of transcription factors . In the present work we have studied the importance of the individual TNFR in silica-induced lung inflammation and matrix deposition in mice. We stud ied RNA expression of TNF, alpha1(I) collagen, interstitial collagenase (MM P-13), and its inhibitor (TIMP-1) in the lungs of silica-treated mice. Furt hermore, we correlated MMP-13/TIMP-1 RNA abundance with activation of the t ranscription factors AP-1 and NF-kappaB in the lungs of C57BL/6 mice, and o f mice deficient in one of the two types of TNFR (p55(-/-) or p75(-/-)), ex posed to silica (0.2 g/kg) or saline by intratracheal instillation. Animals were killed 28 d after exposure and lung hydroxyproline (HP), TNF, alpha1( I) collagen, MMP-13, and TIMP-1 RNA abundance was measured. AP-1 and NF-kap paB activation was studied by gel-shift assays. Compared with C57BL/6 mice, p55(-/-) and p75(-/-) mice significantly (*p < 0.05) decreased lung HP acc umulation in response to silica. All murine strains enhanced TNF and <alpha >1(I) collagen mRNA in response to silica. Enhanced (p < 0.05) MMP-13 RNA e xpression was also observed in all murine strains in response to silica. En hanced (p < 0.05) TIMP-1 RNA expression was observed in C57BL/6 mice, but n ot in p55(-/-) or p75(-/-) mice, in response to silica. NF-KB activation wa s observed in all murine strains, whereas AP-1 activation was observed only in C57BL/6 mice after silica treatment. These data suggest that TNFR delet ion modifies MMP-13/TIMP-1 expression in favor of matrix degradation.