Progressive biliary destruction is independent of a functional tumor necrosis factor-alpha pathway in a rhesus rotavirus-induced murine model of biliary atresia.
Rhesus rotavirus (RRV)-inoculated neonatal BALB/c mice develop an immune-mediated inflammation of extra- and intrahepatic bile ducts that progresses to biliary obstruction and death by 3 wk of age. Livers of diseased animals demonstrate increased numbers of T lymphocytes with elevated expression of helper T cell type 1 (Th1) cytokines at 1 wk, which transitions to increased numbers of macrophages and high expression of the proinflammatory cytokine tumor necrosis factor (TNF)-alpha by 2 wk. We employed both pharmacologic and genetic approaches for attenuation of TNF-alpha to determine whether it plays a causal role in injury. First, RRV-inoculated BALB/c mice were subjected to multiple treatments with either the TNF receptor I (TNF-RI)-Fc fusion protein etanercept or neutralizing antibodies to mouse TNF-alpha. Also, TNF-RI(-/-) mice were injected with RRV in the same manner as wild-type mice. In all cases, TNF inhibition did not reduce the severity or incidence of disease. Survival curves of mice given blocking agents were similar to those of control RRV-inoculated mice, and survival of challenged TNF-RI(-/-) mice was worse than that of wild-type mice, likely because of the prolonged presence of infectious RRV. In all experimental groups, markers of disease were unchanged from those of control mice. In summary, although RRV-inoculated BALB/c mice have highly elevated expression of TNF-alpha, this cytokine does not play an obligate role in disease progression.
Tucker
Rebecca M
RM
Division of Allergy and Clinical Immunology, Department of Medicine, University of Colorado School of Medicine, Denver, Colorado 80262, USA. rebecca.tucker@uchsc.edu
Hendrickson
Richard J
RJ
Mukaida
Naofumi
N
Gill
Ronald G
RG
Mack
Cara L
CL
D000818:Animals; D001656:Biliary Atresia / Q000209:etiology*; D001663:Bilirubin / Q000097:blood; D004195:Disease Models, Animal; D005260:Female; D008253:Macaca mulatta / Q000821:virology*; D051379:Mice; D008807:Mice, Inbred BALB C; D051381:Rats; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000502:physiology; D012400:Rotavirus Infections / Q000150:complications* / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*
D047888:Receptors, Tumor Necrosis Factor, Type I; D014409:Tumor Necrosis Factor-alpha; D001663:Bilirubin