Disparate roles for TNF-alpha and Fas ligand in concanavalin A-induced hepatitis

• Published in: The Journal of immunology (1950) Vol. 160; no. 8; pp. 4082 - 4089
• Main Authors: Ksontini, R, Colagiovanni, D B, Josephs, M D, Edwards, 3rd, C K, Tannahill, C L, Solorzano, C C, Norman, J, Denham, W, Clare-Salzler, M, MacKay, S L, Moldawer, L L
• Format: Journal Article
• Language: English
• Published: United States 15.04.1998
• Subjects: Animals; Apoptosis; Base Sequence; Caspase 1; Chemical and Drug Induced Liver Injury - etiology; Chemical and Drug Induced Liver Injury - immunology; Chemical and Drug Induced Liver Injury - physiopathology; Concanavalin A - toxicity; Cysteine Endopeptidases - deficiency; Cysteine Endopeptidases - physiology; DNA Primers - genetics; Fas Ligand Protein; Liver - drug effects; Liver - immunology; Liver - pathology; Male; Membrane Glycoproteins - antagonists & inhibitors; Membrane Glycoproteins - genetics; Membrane Glycoproteins - physiology; Mice; Mice, Inbred C57BL; Polymerase Chain Reaction; RNA, Messenger - genetics; RNA, Messenger - metabolism; Tumor Necrosis Factor-alpha - antagonists & inhibitors; Tumor Necrosis Factor-alpha - genetics; Tumor Necrosis Factor-alpha - physiology; Up-Regulation - drug effects
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.160.8.4082

Apoptosis is a physiologic process that serves to eliminate cells during development or in response to immunologic regulation. In acute inflammation, however, apoptosis triggered by the overproduction of "death factors" such as TNF-alpha or Fas ligand (FasL) may contribute to tissue injury. Both TNF-alpha and FasL are presumed to convey an apoptotic signal by activating a cascade of cysteine-aspartate proteases, which includes IL-1beta-converting enzyme or caspase-1. In the present study, we evaluated the contribution of TNF-alpha and FasL, as well as the role of caspase-1, in Con A-induced hepatitis. We report here that TNF-alpha and FasL mRNA and protein levels are both increased in the livers of Con A-challenged mice. Using a novel inhibitor of TNF-alpha, we can confirm that Con A-induced hepatitis is primarily TNF-alpha dependent. Blockade of FasL with a soluble Fas immunoadhesin does not prevent liver injury in animals treated with Con A alone. However, administration of a matrix metalloproteinase inhibitor exacerbates liver injury, in part through a FasL-dependent process, since pretreatment with the soluble Fas immunoadhesin reduces liver injury in this model. In addition, mice lacking functional caspase-1 are resistant to Con A-induced hepatitis, even after pretreatment with a matrix metalloproteinase inhibitor. We conclude that TNF-alpha plays a predominant role in Con A-induced liver injury, although concomitant activation of FasL can also lead to apoptotic injury. Furthermore, Con A-induced hepatitis is caspase-1 dependent.