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

Ksontini R, Colagiovanni DB, Josephs MD, Edwards CK, Tannahill CL, Solorzano CC, Norman J, Denham W, Clare-Salzler M, MacKay SL, Moldawer LL
J Immunol. 1998 160 (8): 4082-9

PMID: 9558119

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.

MeSH Terms (18)

Animals Apoptosis Base Sequence Caspase 1 Chemical and Drug Induced Liver Injury Concanavalin A Cysteine Endopeptidases DNA Primers Fas Ligand Protein Liver Male Membrane Glycoproteins Mice Mice, Inbred C57BL Polymerase Chain Reaction RNA, Messenger Tumor Necrosis Factor-alpha Up-Regulation

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