Involvement of 26-kDa Cell-Associated TNF-α in Experimental Hepatitis and Exacerbation of Liver Injury with a Matrix Metalloproteinase Inhibitor

Carmen C. Solorzano, Riadh Ksontini, Jeffrey H. Pruitt, Philip J. Hess, Paul D. Edwards, Atsushi Kaibara, Amer Abouhamze, Troy Auffenberg, Richard E. Galardy, J. Nicolas Vauthey, Edward M. Copeland, Carl K. Edwards, Gregory Y. Lauwers, Michael Clare-Salzler, Sally L D MacKay, Lyle L. Moldawer, Douglas D. Lazarus

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Abstract

TNF-α is a pleiotropic cytokine that exists both as a 26-kDa cell-associated and a 17-kDa soluble form. Recently, a class of matrix metalloproteinase inhibitors has been identified that can prevent the processing by TNF convertase of 26-kDa TNF-α to its 17-kDa form and can reduce mortality from normally lethal doses of D-galactosamine plus LPS (D-GalN/LPS). Here we report that a matrix metalloproteinase inhibitor, GM-6001, improves survival but does not protect against liver injury from D-GalN/ LPS-induced shock in the mouse. In Con A-induced hepatitis, GM-6001 actually exacerbates hepatocellular necrosis and apoptosis despite greater than 90% reduction in plasma TNF-α concentrations. Treatment with GM-6001 also has minimal effect on the concentration of membrane-associated TNF-α in the livers of animals with Con A induced hepatitis. In contrast, a TNF binding protein (TNF-bp), which neutralizes both membrane-associated and soluble TNF-α, prevents D-GalN/LPS- and Con A-induced hepatitis. Our studies suggest that cell-associated TNF-α plays a role in the hepatocellular necrosis and apoptosis that accompany D-CalN/LPS- or Con A-induced hepatitis, and that matrix metalloproteinase inhibitors are ineffective in preventing this hepatic injury.

Original languageEnglish (US)
Pages (from-to)414-419
Number of pages6
JournalJournal of Immunology
Volume158
Issue number1
StatePublished - Jan 1 1997

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Matrix Metalloproteinase Inhibitors
Hepatitis
Galactosamine
Liver
Wounds and Injuries
Necrosis
Apoptosis
Membranes
Shock
Carrier Proteins
Cytokines
Mortality
N-(2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl)-L-tryptophan methylamide

ASJC Scopus subject areas

  • Immunology

Cite this

Solorzano, C. C., Ksontini, R., Pruitt, J. H., Hess, P. J., Edwards, P. D., Kaibara, A., ... Lazarus, D. D. (1997). Involvement of 26-kDa Cell-Associated TNF-α in Experimental Hepatitis and Exacerbation of Liver Injury with a Matrix Metalloproteinase Inhibitor. Journal of Immunology, 158(1), 414-419.

Involvement of 26-kDa Cell-Associated TNF-α in Experimental Hepatitis and Exacerbation of Liver Injury with a Matrix Metalloproteinase Inhibitor. / Solorzano, Carmen C.; Ksontini, Riadh; Pruitt, Jeffrey H.; Hess, Philip J.; Edwards, Paul D.; Kaibara, Atsushi; Abouhamze, Amer; Auffenberg, Troy; Galardy, Richard E.; Vauthey, J. Nicolas; Copeland, Edward M.; Edwards, Carl K.; Lauwers, Gregory Y.; Clare-Salzler, Michael; MacKay, Sally L D; Moldawer, Lyle L.; Lazarus, Douglas D.

In: Journal of Immunology, Vol. 158, No. 1, 01.01.1997, p. 414-419.

Research output: Contribution to journalArticle

Solorzano, CC, Ksontini, R, Pruitt, JH, Hess, PJ, Edwards, PD, Kaibara, A, Abouhamze, A, Auffenberg, T, Galardy, RE, Vauthey, JN, Copeland, EM, Edwards, CK, Lauwers, GY, Clare-Salzler, M, MacKay, SLD, Moldawer, LL & Lazarus, DD 1997, 'Involvement of 26-kDa Cell-Associated TNF-α in Experimental Hepatitis and Exacerbation of Liver Injury with a Matrix Metalloproteinase Inhibitor', Journal of Immunology, vol. 158, no. 1, pp. 414-419.
Solorzano, Carmen C. ; Ksontini, Riadh ; Pruitt, Jeffrey H. ; Hess, Philip J. ; Edwards, Paul D. ; Kaibara, Atsushi ; Abouhamze, Amer ; Auffenberg, Troy ; Galardy, Richard E. ; Vauthey, J. Nicolas ; Copeland, Edward M. ; Edwards, Carl K. ; Lauwers, Gregory Y. ; Clare-Salzler, Michael ; MacKay, Sally L D ; Moldawer, Lyle L. ; Lazarus, Douglas D. / Involvement of 26-kDa Cell-Associated TNF-α in Experimental Hepatitis and Exacerbation of Liver Injury with a Matrix Metalloproteinase Inhibitor. In: Journal of Immunology. 1997 ; Vol. 158, No. 1. pp. 414-419.
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abstract = "TNF-α is a pleiotropic cytokine that exists both as a 26-kDa cell-associated and a 17-kDa soluble form. Recently, a class of matrix metalloproteinase inhibitors has been identified that can prevent the processing by TNF convertase of 26-kDa TNF-α to its 17-kDa form and can reduce mortality from normally lethal doses of D-galactosamine plus LPS (D-GalN/LPS). Here we report that a matrix metalloproteinase inhibitor, GM-6001, improves survival but does not protect against liver injury from D-GalN/ LPS-induced shock in the mouse. In Con A-induced hepatitis, GM-6001 actually exacerbates hepatocellular necrosis and apoptosis despite greater than 90{\%} reduction in plasma TNF-α concentrations. Treatment with GM-6001 also has minimal effect on the concentration of membrane-associated TNF-α in the livers of animals with Con A induced hepatitis. In contrast, a TNF binding protein (TNF-bp), which neutralizes both membrane-associated and soluble TNF-α, prevents D-GalN/LPS- and Con A-induced hepatitis. Our studies suggest that cell-associated TNF-α plays a role in the hepatocellular necrosis and apoptosis that accompany D-CalN/LPS- or Con A-induced hepatitis, and that matrix metalloproteinase inhibitors are ineffective in preventing this hepatic injury.",
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AU - Edwards, Paul D.

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