Intragraft localization of activated nuclear factorκB in recurrent hepatitis C virus disease following liver transplantation

Abstract

Nuclear factor B (NF-B) is activated during viral infection and isAn estimated 170 million people worldwide and nearly 4 million people in the United States alone are infected with the hepatitis C virus (HCV). 1,2 Up to 85% of the individuals infected with HCV develop a chronic disease course associated with an increased risk of cirrhosis and hepatocellular carcinoma. 1,3 Currently, end-stage liver disease secondary to HCV infection is the leading indication for orthotopic liver transplantation (OLTx) in the United States. 4 Recurrence of HCV infection after OLTx of HCV patients is universal and associated with HCV viremia and high intragraft HCV antigen levels. 5-9 More than half of OLTx patients transplanted because of HCV-related disease will develop histopathologic evidence of chronic hepatitis 10-12 and some will develop a severe form of fibrosing cholestatic hepatitis associated with progressive allograft failure, 13,14 whereas others will develop allograft cirrhosis 15 and de novo hepatocellular carcinoma. 16 The specific pathogenetic mechanisms contributing to recurrent HCV infection and disease progression in immunocompromised transplant patients remain ill defined. Worse yet, the limited understanding of the pathogenesis of HCV infection in immunocompetent individuals provides little insight into the development of a successful therapeutic strategy for transplant recipients infected with the HCV.Substantial evidence has implicated a pivotal role for liver-specific immune-mediated mechanisms that include the production of inflammatory mediators and activation of host effector cells, in the development and progression of the liver injury associated with chronic HCV infection in immunocompetent individuals. [17][18][19][20] Moreover, recent investigations have documented a low number of apoptotic hepatocytes in HCV-infected liver tissue, 21-23 perhaps as a critical mechanism whereby uninhibited viral replication can occur. 24,25 The transcription factor nuclear factor B (NF-B), initially identified as an inducer of B-cell-specific gene expresssion, 26 is known to regulate the HCV-specific expression of several inflammatory mediator genes and inhibition of apoptotic cell death, which may influence the replication of HCV and the

NF-kappaB, p38 MAPK and JNK are highly expressed and active in the stroma of human colonic adenomatous polyps

“…We show that immunoreactivity of these two molecules is also seen in macrophages in colonic polyps. The same anti active NF-kB antibody has been used to perform immunohistochemistry in formalin ®xed, para n embedded tissue in other studies including several that have shown activated NF-kB in macrophages (Gaweco et al, 2000;Rogler et al, 1998). We ourselves have previously shown the speci®city of this antibody under the same conditions by showing colocalisation of TNFa, TRAF-2 and total NF-kB staining with the active NF-kB staining and showing clear nuclear localisation of the active NF-kB (van Den Brink et al, 2000).…”

Resistin as an Intrahepatic Cytokine

“…Of note, increased NF-B activation has been documented in human liver tissue from patients with nonalcoholic steatohepatitis, HCV infection, or alcohol-induced liver disease. 51,52 In rodents with dietinduced or genetic obesity, increased intrahepatic activation of NF-B is associated with up-regulation of proinflammatory cytokines, and inhibition of NF-B ameliorates insulin resistance. 53,54 Accordingly, transgenic mice with low-level, liver-specific activation of NF-B have recently been shown to develop insulin resistance both in the liver and systemically, even in the absence of obesity or steatosis.…”

Rotavirus-induced murine biliary atresia is mediated by nuclear factor-κB

“…NF-jB proteins are sequence-specific transcription factors that control a variety of important biologic decisions including the activation of inflammatory and innate immune response to the virus infection [10][11][12][13][14]16,17]. Nuclear factorjB exists as homodimers and heterodimers of various subunits of the Rel family of protein with the prototypical NF-jB dimer consisting of both a p50 and a p65 (Rel) subunit [18].…”

“…High immunoreactivity of NF-jB had been demonstrated in Kupffer cells and macrophages of all specimens of orthotopic liver transplantation patients with recurrent hepatitis C virus, contrasted to the weak staining in controls. From these observations, it may be concluded that NF-jB activation plays an immunoregulatory role in the pathogenesis and progression of recurrent hepatitis C virus after liver transplantation [10]. It had also been demonstrated that the expression of different proteins of influenza virus induced the activation of NF-jB -dependent gene expression [11].…”