| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
ß-Induced Antiviral Activity and STAT1 Activation in the Liver: Involvement of Proteasome-Dependent Pathway1
*
Department of Pharmacology and Toxicology, Medical College of Virginia Commonwealth University, Richmond, VA 23298; and
Shandong Cancer Biotherapy Center, Shandong Academy of Medical Sciences, Jinan, China
IFN-
ß is the only established treatment for viral hepatitis;
however, more than 60% of patients are poorly responsive. Because
viral hepatitis is associated with inflammation, we hypothesized that
inflammation may attenuate the efficacy of IFN therapy. To test this
hypothesis, the effect of IL-1ß, one of the major proinflammatory
cytokines, on IFN signaling pathway in the liver was examined.
Administration of IL-1ß in vivo attenuated IFN-ß-induced STAT1
tyrosine phosphorylation in the liver but not in the spleen. The
inhibitory action of IL-1ß in vivo was not affected by depleting
hepatic Kupffer cells, suggesting that IL-1ß may directly target
IFN-ß signaling in hepatocytes. Indeed, pretreatment of human
hepatocellular carcinoma HepG2 cells with IL-1ß suppressed
IFN-ß-induced antiviral activity and antiviral protein MxA mRNA
expression. Furthermore, IL-1ß attenuated IFN-ß-induced STAT1
binding and tyrosine phosphorylation without affecting the level of
STAT1 protein. This inhibitory effect can be reversed by pretreatment
with either proteasome inhibitors or transfection of dominant negative
NF-
B inducing kinase mutants. Taken together, these findings suggest
that IL-1ß attenuates IFN-ß-induced STAT1 activation by a
proteasome-dependent mechanism. In view of high levels of IL-1ß in
the serum or within the liver of patients with chronic liver diseases,
attenuation of IFN-ß signaling in the liver by IL-1ß could be
one of the mechanisms underlying the resistance to IFN therapy in
chronic hepatitis C, and IL-1ß could be a potential therapeutic
target for improving the efficacy of IFN
therapy.
This article has been cited by other articles:
|
|
 |
|
  C. Dunn, M. Brunetto, G. Reynolds, T. Christophides, P. T. Kennedy, P. Lampertico, A. Das, A. R. Lopes, P. Borrow, K. Williams, et al. Cytokines induced during chronic hepatitis B virus infection promote a pathway for NK cell-mediated liver damage J. Exp. Med., March 19, 2007; 204(3): 667 - 680. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Ahmad and F. Alvarez Role of NK and NKT cells in the immunopathogenesis of HCV-induced hepatitis J. Leukoc. Biol., October 1, 2004; 76(4): 743 - 759. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.-D. Ji, I. Tassiulas, K.-H. Park-Min, A. Aydin, I. Mecklenbrauker, A. Tarakhovsky, L. Pricop, J. E. Salmon, and L. B. Ivashkiv Inhibition of Interleukin 10 Signaling after Fc Receptor Ligation and during Rheumatoid Arthritis J. Exp. Med., June 2, 2003; 197(11): 1573 - 1583. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Zhu and C. Liu Interleukin-1 Inhibits Hepatitis C Virus Subgenomic RNA Replication by Activation of Extracellular Regulated Kinase Pathway J. Virol., May 1, 2003; 77(9): 5493 - 5498. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Jirillo, D. Caccavo, T. Magrone, E. Piccigallo, L. Amati, A. Lembo, C. Kalis, and M. Gumenscheimer Review: The role of the liver in the response to LPS: experimental and clinical findings Innate Immunity, October 1, 2002; 8(5): 319 - 327. [Abstract] [PDF]
|
|
|
|
|
|
S. T. Ahmed, A. Mayer, J.-D. Ji, and L. B. Ivashkiv Inhibition of IL-6 signaling by a p38-dependent pathway occurs in the absence of new protein synthesis J. Leukoc. Biol., July 1, 2002; 72(1): 154 - 162. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
