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 studied RNA expression of TNF, alpha1(I) collagen, interstitial collagenase (MMP-13), and its inhibitor (TIMP-1) in the lungs of silica-treated mice. Furthermore, we correlated MMP-13/TIMP-1 RNA abundance with activation of the transcription factors AP-1 and NF-kappaB in the lungs of C57BL/6 mice, and of mice deficient in one of the two types of TNFR (p55(-/-) or p75(-/-)), exposed 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-kappaB activation was studied by gel-shift assays. Compared with C57BL/6 mice, p55(-/-) and p75(-/-) mice significantly (*p < 0.05) decreased lung HP accumulation in response to silica. All murine strains enhanced TNF and alpha1(I) collagen mRNA in response to silica. Enhanced (p < 0.05) MMP-13 RNA expression was also observed in all murine strains in response to silica. Enhanced (p < 0.05) TIMP-1 RNA expression was observed in C57BL/6 mice, but not in p55(-/-) or p75(-/-) mice, in response to silica. NF-kappaB activation was observed in all murine strains, whereas AP-1 activation was observed only in C57BL/6 mice after silica treatment. These data suggest that TNFR deletion modifies MMP-13/ TIMP-1 expression in favor of matrix degradation.
Ortiz
L A
LA
Section of Pulmonary Diseases, Critical Care, and Environmental Medicine, Department of Pathology, and the Lung Biology Program, Tulane University Medical Center, New Orleans, Louisiana 70112-2699, USA. lortiz@mailhost.tcs.tulane.edu
Lasky
J
J
Gozal
E
E
Ruiz
V
V
Lungarella
G
G
Cavarra
E
E
Brody
A R
AR
Friedman
M
M
Pardo
A
A
Selman
M
M
D000818:Animals; D003094:Collagen / Q000032:analysis; D017364:Collagenases / Q000378:metabolism*; D005260:Female; D008168:Lung / Q000737:chemistry; D020781:Matrix Metalloproteinase 1 / Q000096:biosynthesis*; D053509:Matrix Metalloproteinase 13; D051379:Mice; D008810:Mice, Inbred C57BL; D018124:Receptors, Tumor Necrosis Factor / Q000172:deficiency*; D012829:Silicosis / Q000201:enzymology*
D018124:Receptors, Tumor Necrosis Factor; D003094:Collagen; D017364:Collagenases; D053509:Matrix Metalloproteinase 13; C507081:Mmp13 protein, mouse; D020781:Matrix Metalloproteinase 1