We report in this study that expression of CD137L is usually substantially upregulated in peripheral CD14+ monocytes of CHB patients and is closely associated with liver cirrhosis. MCP-1. Importantly, the natural ligand of CD137 was upregulated significantly in circulating CD14+ monocytes in patients with chronic hepatitis B contamination and closely correlated with development of liver cirrhosis. Thus, sustained CD137 activation may be a contributing factor for liver immunopathology in chronic HBV contamination. Our studies reveal a common molecular pathway that is used to defend against viral contamination but also causes chronic hepatic diseases. Prolonged contamination with hepatitis B computer virus (HBV) predisposes to the development of chronic inflammatory liver diseases, which often progress to hepatic cirrhosis and hepatocellular carcinoma (HCC) (1). Because HBV is not directly cytolytic for the hepatocyte, liver diseases are thought to be immune mediated. HBV-specific CD8+ CTLs were demonstrated to play a critical role in viral clearance in acute infection or the early stage of liver diseases (2, 3). However, this response is clearly blunted in chronic HBV contamination, with scanty responses of low frequency and limited specificity (4, 5). Patients with chronic hepatitis B (CHB) often have large lymphocytic infiltration in the livers with a high ratio of CD8+ T cells that are not specific for HBV and often have memory phenotype (4). However, the GKA50 characteristics of these CD8+ T cell populations and their potential contribution to liver immunopathology are largely unknown. A recent statement indicated that circulating and intrahepatic GKA50 CD8+ T cells from CHB patients, regardless of their Ag specificity, are impaired in their ability to produce IL-2 and to proliferate upon activation by Ag. However, these CD8+ T cells retain the capacity to produce proinflammatory cytokines IFN- and TNF-, which persist even in the patients with high viral weight and liver inflammation (6). CD137 (4-1BB) is an inducible cosignaling receptor of the TNFR superfamily, which is usually expressed on the surface of activated T cells, NK cells, macrophages, and dendritic cells (7). Its ligand, CD137L, is usually constitutively expressed on a portion of dendritic cells and is inducible mainly on activated monocytes, macrophages, B cells, and Rabbit Polyclonal to NudC a small fraction of T cells (8). Engagement of CD137 provides a costimulatory transmission to induce T cell growth, production of IFN-, and prevention of activation-induced death of effector T cells (9), leading to enhanced T cell responses against viral contamination in animal models (10, 11). We showed recently that CD137 activation by an agonist mAb in the absence of Ag induces vigorous growth and cytokine production from CD8+ and CD4+ T cells with memory phenotype in naive mice, whereas the same activation does not impact naive T cells (12). Given the possible role of CD137 in Ag-independent activation of memory T cells, we speculate that enhanced CD137 activation may activate HBV-nonspecific memory T cells, leading to chronic inflammation and pathogenesis of liver diseases. We statement in this GKA50 study that expression of CD137L is usually substantially upregulated in peripheral CD14+ monocytes of CHB patients and is closely associated with liver cirrhosis. Using an agonist CD137 mAb as mimicry of CD137L, we examined the consequence of CD137 activation on liver inflammation and disease progression in HBV-transgenic mice. Materials and Methods Subjects Ten milliliters of venous blood was drawn from 61 patients with chronic HBV contamination (serum positive for hepatitis B surface Ag [HBsAg] for 12 mo) and 31 healthy donors (HBsAg unfavorable, anti-HBc unfavorable, and anti-HBe unfavorable). The patients were divided into two groups with respect to the pathological index of liver cirrhosis, the typical morphologic findings on computed tomography or ultrasound, symptoms of portal hypertension, and liver biopsies: 40 patients with liver cirrhosis and 21 patients without cirrhosis. No individual experienced received anti-HBV brokers or immunosuppressive drugs 6 mo before sampling. Patients who experienced HIV and other types of chronic liver diseases, such as hepatitis C computer virus, chronic hepatitis E, alcoholic liver disease, or steatohepatitis, were excluded from the current study. The study protocol was approved by the Ethics Committees of the institutions, and knowledgeable consent was obtained from all participants before sample collection. The characteristics of the patients and healthy donors are outlined in Supplemental Table I. Experimental animals HBV-transgenic mice C57BL/6J-TgN (Alb1 HBV)44Bri, which express part of the HBV genome, including S, pre-S, and X genes under the mouse albumin promoter, were purchased from your Jackson Laboratory (Bar Harbor, ME). The mice were matched for sex and age (6C8 wk), and the HBV-transgenic mice and their wild-type (WT) littermates were used. The mice were maintained under specific pathogen-free conditions in the animal facility at the Institute of Biophysics, Chinese Academy of Sciences. All studies including animals were.