title: Disparate roles for TNF-alpha and Fas ligand in concanavalin A-induced hepatitis.
abstract: 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.
authors.affiliation: Department of Surgery, University of Florida College of Medicine, Gainesville 32610, USA.
authors.forename: R
authors.initials: R
authors.lastname: Ksontini
authors.forename: D B
authors.initials: DB
authors.lastname: Colagiovanni
authors.forename: M D
authors.initials: MD
authors.lastname: Josephs
authors.forename: C K
authors.initials: CK
authors.lastname: Edwards
authors.forename: C L
authors.initials: CL
authors.lastname: Tannahill
authors.forename: C C
authors.initials: CC
authors.lastname: Solorzano
authors.forename: J
authors.initials: J
authors.lastname: Norman
authors.forename: W
authors.initials: W
authors.lastname: Denham
authors.forename: M
authors.initials: M
authors.lastname: Clare-Salzler
authors.forename: S L
authors.initials: SL
authors.lastname: MacKay
authors.forename: L L
authors.initials: LL
authors.lastname: Moldawer
mesh_terms: D000818:Animals; D017209:Apoptosis; D001483:Base Sequence; D020170:Caspase 1; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology / Q000276:immunology* / Q000503:physiopathology; D003208:Concanavalin A / Q000633:toxicity*; D003546:Cysteine Endopeptidases / Q000172:deficiency / Q000502:physiology; D017931:DNA Primers / Q000235:genetics; D053222:Fas Ligand Protein; D008099:Liver / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D008297:Male; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D017931:DNA Primers; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D003208:Concanavalin A; D003546:Cysteine Endopeptidases; D020170:Caspase 1