Acute Phase Graft Injury Mobilizes Regulating B Cells after Living Donor Liver Transplantation for the Patients with Hepatocellular Carcinoma through TLR4/CXCL10/CXCR3 Signaling
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Background and Objective: The circulating immune cells mobilized during liver transplantation may play important roles in acute phase graft injury and late phase tumor recurrence. However, the precise mechanism of circulating immune cell mobilization during liver transplantation has not been explored. In the current study, we aim to investigate the impact of acute-phase small-for-size graft injury on mobilization of circulating regulating B cells (Bregs) in the patients with hepatocellular carcinoma (HCC) after liver transplantation and to explore the underlying molecular mechanism therein. Methods: From May 2000 to November 2009, 115 HCC recipients were included in the current analysis. The intragraft gene expression profile together with Bregs intragraft infiltration were compared between the recipients implanted with liver grafts greater (Group 1) and less than 60% (Group 2) of standard liver weight (SLW) by real-time RT-PCR and immunostaining, respectively. Circulating Bregs (CD19+CD24hiCD38hi) were detected by FACS analysis at different time points after liver transplantation. Clinical-pathological data including the incidence of tumor recurrence and metastasis were compared between the two groups. The direct roles of TLR4, CXCL10 and CXCR3 on circulating Bregs mobilization were further investigated in TLR4-/-, CXCL10-/- and CXCR3-/- mice models, respectively. The association of intragraft Bregs infiltration and tumor invasiveness were also examined in the rat liver transplantation for liver cancer model. The role of Bregs on liver tumor growth and invasiveness were further studied in a series of in vitro and in vivo functional experiments. Results: The patients were grouped into Group 1 (>= 60% SLW, n=37) and Group 2 (< 60% SLW, n=78). The numbers of patients beyond Milan criteria [15/37(40.5%) vs 29/49(59.2%), p=0.838] or UCSF criteria [9/37(24.3%) vs 19/60(31.7%), p=1] were similar in the two groups. Much more patients in Group 2 developed tumor recurrence and lung metastasis [19/78(24.4%) vs 3/37(8%), p=0.04]. The level of circulating Bregs was significantly higher in Group 2 (Week1: 7.02 vs 1.31/10ˆ5PBMC, p=0.03; month3: 5.7 vs 1.3/10ˆ5PBMC, p=0.03). There was more intragraft Bregs infiltration in group 2 indicated by CD20/IL10 staining. Intragraft gene expression of TLR4, CXCL10 and CXCR3 were significantly higher in Group 2 at early phase after transplantation. In rat liver transplantation model, there was more Bregs infiltration at early phase after transplantation correlating with late phase invasive tumor growth. Levels of circulating Bregs were significantly lower in the mice model with major hepatectomy and hepatic I/R injury using TLR4-/-, CXCL10-/- and CXCR3-/- mice, respectively. In the in vitro co-culture system, Bregs enhanced liver cancer cell proliferation and migration. In the scid mice liver cancer model, Bregs injection significantly promoted tumor growth. Conclusion: A significantly higher population of circulating Bregs, which are mobilized by small-for-size graft injury, may lead to a higher incidence of tumor recurrence and metastasis after LDLT. TLR4/CXCL10/CXCR3 signaling may play important roles on Bregs mobilization.Keywords:
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C-X-C motif chemokine receptor 3 (CXCR3) is a G protein-coupled receptor for three ligands which are C-X-C motif chemokine 9 (CXCL9), CXCL10, and CXCL11 [1]. Previously we have reported that CXCL10 promotes pro-inflammatory cytokine expression, and forms positive feedback loop [2], [3]. In the present study, we described mRNA expression of CXCL9 and CXCL11 under CXCL10 stimuli in the presence or absence of CXCR3 antagonist, JN-2 in bone marrow-derived macrophages (BMMs) and CD4+ T cells. In addition, we examined pro-inflammatory cytokine expression under CXCL9 or CXCL11 stimuli in BMMs and CD4+ T cells.
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The role of chemokines in virus-induced acute hepatic failure is not well defined. In this study, we investigated the role of CXC chemokine receptor 3 (CXCR3) and its ligands chemokine Mig/CXCL9 (monokine induced by IFN-gamma) and IP-10/CXCL10 (interferon-gamma-inducible protein 10) in the recruitment of intrahepatic lymphocytes and subsequent acute hepatic failure. Balb/cJ mice (6 to 8 weeks, female) were intraperitoneally injected with 100 PFU murine hepatitis virus strain 3 (MHV-3). The proportions and numbers of T cells and NK cells in liver, spleen, and blood as well as the expression of CXCR3 on T cells and NK cells post MHV-3 infection was analyzed by flow cytometry. The hepatic mRNA level of the CXCR3-associated chemokines (CXCL9 and CXCL10) was detected by realtime PCR. A transwell migration assay was used to assess the chemotactic effect of MHV-3-infected hepatocytes and CXCL10 on the splenic lymphocytes. Following MHV-3 infection, the number of hepatic NK cells and T cells and the frequencies of hepatic NK cells and T cells expressing CXCR3 increased markedly; however, in the spleen and peripheral blood, they both decreased significantly. Moreover, the hepatic mRNAs levels of CXCL9 and CXCL10 were significantly elevated post infection. The transwell migration assay demonstrated that MHV-3-infected hepatocytes have the capacity to attract and recruit the splenic NK cells and T cells, and CXCL10 plays a key role in lymphocyte mobilization from the spleen. These results indicate that interactions involving CXCR3 and its ligands (CXCL9 and CXCL10), especially CXCL10 may play a key role in the recruitment of intrahepatic lymphocytes and subsequent necroinflammation and acute hepatic failure. Key words: Chemokine, interferon gamma-inducible protein 10 (CXCL10), hepatic failure, natural killer cell, T cell.
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The aim of this study is to present direct evidence for the involvement of CXC chemokine ligand 10 (CXCL10) and CXCR3 in human autoimmune type 1 diabetes. We examined five patients with recent-onset type 1 diabetes and five control subjects without diabetes. Islet cell antibodies or GAD antibodies or both were detected in all five patients. We used double-immunofluorescence to detect the expression of CXCL10 and CXCR3 (the receptor of CXCL10). CXCL10 was detected in the islets of all five patients. Almost all (84.2 ± 10.3 %, mean ± SD) CXCL10-positive cells were insulin-positive in the islet area. CXCL10-positive cells with glucagons, somatostatins or pancreatic polypeptides were not detected at all. CXCL10 expression was not seen in any islet without beta cells. CXCR3 was detected in the islet areas of all five patients. Almost all (80.3 ± 13.4 %, mean ± SD) CXCR3-positive cells were CD3-positive T cells. Our study showed that CXCL10 was expressed in the remaining beta cells, and the infiltrating T cells expressed CXCR3, in pancreatic islets of patients with recent-onset type 1 diabetes. The interaction of CXCL10 and CXCR3 would contribute to the selective destruction of beta cells in the development of type 1 diabetes.
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AIM:To investigate the immunologic mechanism of CXC chemokine ligand 10(CXCL10) and its receptor CXC chemokine receptor 3(CXCR3) involved in the process of endometriosis (EM). METHODS:Serum samples were collected from 3 groups:EM patients without operation (n=76),EM patients with operation (n=10) and the normal control persons (n=76). CXCL10 and CA125 concentrations were detected by means of ELISA and chemiluminometry. Cell surface antigens on the activated PBMC-CD3 and CXCR3,as well as CXCR3 subgene-CXCR3A and CXCR3B were tested by flow cytometry (FC) and RT-PCR when PBMC was separated from women with EM (n=10) and without EM (n=10),and then activated. RESULTS:Serum CXCL10 concentrations between three groups were significanly different (P0.05). Compared to normal control group,although the supernatant CXCL10 concentration and CD3+/CXCR3+PBMC number in EM group has no significant difference (P0.05),highly expressed CXCR3B in EM group rather than CXCR3A was observed. CONCLUSION:CXCL10 in women with EM is low,indicating that it plays a vital role in the process of EM and immune system of the women with EM is defected and impaired. The immunoreactivity of PBMC from both EM patients and normal person is same to activated signal,but the productions are different:PBMC in EM group mainly express CXCR3B but PBMC in normal person mainly express CXCR3A after activation,which may be one of the immune mechanisms that EM escapes from immunological lethal effect of the infected host.
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C-X-C motif ligand 10 (CXCL10), or interferon-inducible protein-10, is a small chemokine belonging to the CXC chemokine family. Its members are responsible for leukocyte trafficking and act on tissue cells, like endothelial and vascular smooth muscle cells. CXCL10 is secreted by leukocytes and tissue cells and functions as a chemoattractant, mainly for lymphocytes. After binding to its receptor CXCR3, CXCL10 evokes a range of inflammatory responses: key features in cardiovascular disease (CVD). The role of CXCL10 in CVD has been extensively described, for example for atherosclerosis, aneurysm formation, and myocardial infarction. However, there seems to be a discrepancy between experimental and clinical settings. This discrepancy occurs from differences in biological actions between species (e.g. mice and human), which is dependent on CXCL10 signaling via different CXCR3 isoforms or CXCR3-independent signaling. This makes translation from experimental to clinical settings challenging. Furthermore, the overall consensus on the actions of CXCL10 in specific CVD models is not yet reached. The purpose of this review is to describe the functions of CXCL10 in different CVDs in both experimental and clinical settings and to highlight and discuss the possible discrepancies and translational difficulties. Furthermore, CXCL10 as a possible biomarker in CVD will be discussed.
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