There was no significant difference in Tim-3+ cells among different clinical stages, Child Pugh Scores, or tumor differentiation stages (Table 1). HCC patients were divided into low (<7, n = 42) and high (>7, n = 57) groups based on the median levels of Tim-3+ cells. Log-rank analysis demonstrated that the high Tim-3-expressing group experienced shorter survival when compared to the low Tim-3-expressing group (Fig. 2E). The Tim-3+ cell number was positively selleck screening library associated

with tumor size (P < 0.05) but no correlation to any other parameters (including age, gender, α-fetal protein level, tumor multiplicity, vascular invasion, intrahepatic metastasis, and tumor TNM stage) (Table 1). Multivariate analysis revealed that the number of Tim-3+ cells in HCC tissues was a negative prognostic factor of overall survival. To understand

the functionality of Tim-3+CD4+ T cells in HCC, we examined Z-VAD-FMK chemical structure their phenotype, cytokine profile, and cell cycling genes. We observed that Tim-3+CD4+ T cells were basically confined to CD45RA− and CD62L− T cells (Fig. 3A), suggesting that Tim-3+CD4+ T cells are memory cells. Next, we compared the in vivo proliferation potential and activation status of Tim-3+CD4+ T cells versus Tim-3−CD4+ T cells in HCC. Ki67 and HLA-DR are markers of cell proliferating and activation, respectively. There were fewer Ki67+ cells and HLA-DR+ cells in Tim-3+CD4+ T cells than Tim-3−CD4+ T cells (Fig. 3A,B). This suggests that Tim-3+CD4+ T cells

have reduced proliferation and activation potential in HCC. PD-1 has been identified as a marker for functionally exhausted T cells in HCC.7 We found that Tim-3+ and PD-1+ T cells were two different T-cell subsets with minimal overlapping in HCC. In addition, 上海皓元医药股份有限公司 Tim-3+CD4+ T cells did not express interleukin (IL)-4, IL-17, or Foxp3 (Fig. 3A). Tumor-infiltrating Tim-3+CD4+ T cells expressed less IL-2 and IFN-γ as compared to Tim-3−CD4+ T cells (Fig. 3A,B). Together, the data indicate that HCC infiltrating Tim-3+CD4+ T cells are different from Foxp3+ regulatory T cells, functionally exhausted PD-1+ cells, and Th2 and Th17 cells. Tim-3+CD4+ T cell is a unique T-cell population with poor effector function and reduced proliferating potential in HCC. Low expression of CD28 and high expression of CD57 are thought to be associated with T-cell senescence.38 To determine if Tim-3 expression is linked to T-cell senescence in HCC, we examined the relationship between the expression of CD28, CD57, and Tim-3 on tumor-infiltrating T cells. We showed that there were more CD57+CD28− cells and fewer CD57−CD28+ cells in tumor-infiltrating Tim-3+CD4+ T cells than Tim-3−CD4+ T cells (Fig. 3C). The results suggest that Tim-3+CD4+ T cells may contain senescent cells with limited proliferating potential. Given that Tim-3+CD4+ T cells were less proliferative and contained senescent cells, we further quantified the expression of key genes controlling cell cycle and cellular senescence.

There was no significant difference in Tim-3+ cells among different clinical stages, Child Pugh Scores, or tumor differentiation stages (Table 1). HCC patients were divided into low (<7, n = 42) and high (>7, n = 57) groups based on the median levels of Tim-3+ cells. Log-rank analysis demonstrated that the high Tim-3-expressing group experienced shorter survival when compared to the low Tim-3-expressing group (Fig. 2E). The Tim-3+ cell number was positively BGJ398 associated

with tumor size (P < 0.05) but no correlation to any other parameters (including age, gender, α-fetal protein level, tumor multiplicity, vascular invasion, intrahepatic metastasis, and tumor TNM stage) (Table 1). Multivariate analysis revealed that the number of Tim-3+ cells in HCC tissues was a negative prognostic factor of overall survival. To understand

the functionality of Tim-3+CD4+ T cells in HCC, we examined I-BET-762 in vivo their phenotype, cytokine profile, and cell cycling genes. We observed that Tim-3+CD4+ T cells were basically confined to CD45RA− and CD62L− T cells (Fig. 3A), suggesting that Tim-3+CD4+ T cells are memory cells. Next, we compared the in vivo proliferation potential and activation status of Tim-3+CD4+ T cells versus Tim-3−CD4+ T cells in HCC. Ki67 and HLA-DR are markers of cell proliferating and activation, respectively. There were fewer Ki67+ cells and HLA-DR+ cells in Tim-3+CD4+ T cells than Tim-3−CD4+ T cells (Fig. 3A,B). This suggests that Tim-3+CD4+ T cells

have reduced proliferation and activation potential in HCC. PD-1 has been identified as a marker for functionally exhausted T cells in HCC.7 We found that Tim-3+ and PD-1+ T cells were two different T-cell subsets with minimal overlapping in HCC. In addition, 上海皓元 Tim-3+CD4+ T cells did not express interleukin (IL)-4, IL-17, or Foxp3 (Fig. 3A). Tumor-infiltrating Tim-3+CD4+ T cells expressed less IL-2 and IFN-γ as compared to Tim-3−CD4+ T cells (Fig. 3A,B). Together, the data indicate that HCC infiltrating Tim-3+CD4+ T cells are different from Foxp3+ regulatory T cells, functionally exhausted PD-1+ cells, and Th2 and Th17 cells. Tim-3+CD4+ T cell is a unique T-cell population with poor effector function and reduced proliferating potential in HCC. Low expression of CD28 and high expression of CD57 are thought to be associated with T-cell senescence.38 To determine if Tim-3 expression is linked to T-cell senescence in HCC, we examined the relationship between the expression of CD28, CD57, and Tim-3 on tumor-infiltrating T cells. We showed that there were more CD57+CD28− cells and fewer CD57−CD28+ cells in tumor-infiltrating Tim-3+CD4+ T cells than Tim-3−CD4+ T cells (Fig. 3C). The results suggest that Tim-3+CD4+ T cells may contain senescent cells with limited proliferating potential. Given that Tim-3+CD4+ T cells were less proliferative and contained senescent cells, we further quantified the expression of key genes controlling cell cycle and cellular senescence.

“
“Upper gastrointestinal endoscopy is a procedure that allows for visualization

of the esophagus, stomach and proximal small bowel. There are a variety AZD5363 clinical trial of technical and cognitive aspects that must be mastered in order to perform a high quality examination. The aim of this chapter is to describe the elements of a complete and thorough upper endoscopy, and to review the key elements of that procedure, including tissue sampling. “
“I read with interest the updated practice guidelines for the management of hepatocellular carcinoma (HCC) by the American Association for the Study of Liver Diseases.1 It is undeniable that the Barcelona Clinic Liver Cancer staging system has become widely accepted in clinical practice. However, the management options for each stage appear to be too rigidly restricted. For example, percutaneous ethanol injection (PEI) can be considered for patients with liver nodules that are inaccessible to radiofrequency ablation, but in comparison with either treatment as monotherapy, the combination of radiofrequency ablation and PEI has been shown to be more effective for long-term survival.2 For intermediate-stage patients, transarterial chemoembolization (TACE) seems to be

the treatment of choice. However, in comparison with TACE alone, the combination of TACE and Selleckchem ABT-888 PEI has been demonstrated to prolong survival in patients with small lesions and in patients with advanced lesions.3, 4 On the other hand, although the use of sorafenib in patients with advanced HCC has been proven to prolong survival, the reported partial response rate is only 2%, and no patients have achieved a complete response.5 Our group has demonstrated that an intra-arterial infusion of chemotherapy can lead to a complete response in 9.4% of patients with advanced HCC and to a partial response in 18.9%.6 Thus, for patients with advanced HCC, an intra-arterial

infusion of chemotherapy is a viable alternative to sorafenib. Gin-Ho Lo M.D.*, * Digestive Center, Department of Medical Education, E-Da Hospital, I-Shou University, Kaohsiung, Taiwan. “
“BACKGROUND: Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide. Over 600,000 new cases are diagnosed each year. Early stage disease can be cured with surgical resection or liver transplantation. Liver MCE transplantation offers the best chance at a cure; however, recurrence rates are as high as 40% for those transplanted. The enumeration of circulating tumor cells (CTCs) is an independent prognostic biomarker in patients with malignancies including breast and colon cancer. CTCs in the peripheral blood of HCC patients have been correlated to tumor size, portal vein tumor thrombosis, and stage. There is no data regarding the utility of CTC identification and molecular characterization to predict patients at high risk of HCC recurrence.

Portal blood flow in humans is approximately 1000–1200 mL/min. Thus, the liver constantly confronts food-derived

antigens and bacterial components such as lipopolysaccharide (LPS) translocated from the gut into the portal vein; however, the liver has the unique capacity to induce immune tolerance. Previously, regulatory T cells (Treg), Kupffer cells, natural killer T (NKT) cells and hepatic stellate cells (HSC) were reported to contribute to immune tolerance in the liver. Interaction between Treg and Kupffer cells promotes the secretion of interleukin (IL)-10 from Treg, and the depletion of Treg breaks antigen-specific immune tolerance.[2] The depletion of liver NKT cells also exacerbates hepatic inflammation in carbon tetrachloride-induced liver injury.[3] HSC induce the apoptosis STAT inhibitor of conventional CD4+ T cells in a Fas/Fas ligand-dependent manner and increase Treg proliferation via cell–cell contact; moreover, HSC-expanded Treg express high levels of programmed cell death 1 and cytotoxic T-lymphocyte antigen 4, show enhanced production of IL-10, and cause the suppression of alloreactive CD4+ T-cell proliferation.[4] Toll-like receptors (TLR), which comprise a highly conserved

family of receptors that recognizes specific pathogen-associated molecular patterns (PAMP), play a key role in innate immunity by triggering inflammatory responses 上海皓元 to the main ligands of TLR. Various TLR are expressed on liver cells (Table 1). The liver constantly encounters various antigens, and in order to prevent organ failure due to hyperactivation of JAK activation the immune system, TLR tolerance to repeated stimuli is induced.[11] On the other hand, a breakdown in TLR tolerance

results in persistent inflammation and contributes to the development of chronic liver diseases. Singh et al.[12] reported that bacterial translocation comparably occurs in both normal and diseased livers such as primary biliary cirrhosis (PBC) and non-alcoholic steatohepatitis (NASH) although the expression of TLR2 and TLR4 is enhanced in the diseased livers than normal. In normal biliary epithelial cells (BEC), repeated LPS-stimuli induced hyporeactivity to LPS.[13] However, BEC from PBC patients show hyperreactivity to LPS.[14] Herein, we review the association of gut microbiota with the pathogenesis of chronic liver diseases such as NASH, primary sclerosing cholangitis (PSC) and PBC. NON-ALCOHOLIC FATTY LIVER disease (NAFLD) is recognized as a common liver disorder that represents the hepatic manifestation of metabolic syndrome, and encompasses a spectrum of hepatology, ranging from simple steatosis to cirrhosis.[15, 16] NASH is the progressive form of liver injury and characterized by steatosis, lobular inflammation, hepatocyte ballooning, Mallory’s hyaline and fibrosis.

6, p=0.07) and Edmondson grade 3/4 (OR 2.9, p=0.06) to correlate with S1 tumors. Predictive scores were significantly associated with S2 (p<0.001) and S3 (p<0.001) tumors in the validation set, suggesting that the histopathologic features can be used to classify HCC tumors into the 3 subclasses. Gene signatures of Hoshida HCC Subclass S1, cellular hypoxia pathway (which is known to promote lipogenesis), epithelial-mesenchymal transition,

TGF-p activation and oncoprotein YAP signaling were enriched in SH-CC (false discovery rate <0.05). Conclusions: Histopathologic features correlated well with molecular subclasses, and are accompanied with molecular pathway deregulations that potentially contribute to formation of the morphological characteristics. Selleck BYL719 Multivariable model of histopathologic features may serve as a clinical tool to predict molecular subclass of HCC, which could find more inform therapeutic decision in clinic. Disclosures: The following people have nothing to disclose: Poh Seng Tan, Anu Venkatesh, Stephen C. Ward, Claudia

Canasto-Chibuque, Anna Koh, Venugopalan Nair, Manjeet Deshmukh, Shigeki Nakagawa, Xiaochen Sun, Masahiro Kobayashi, Hiromitsu Kumada, Yujin Hoshida Background: Recent evidence suggests that some hepatocellular carcinomas (HCCs) are hierarchically organized, with a subset of cells that possess stem cell features, called cancer stem cells (CSCs). CSCs show chemoresistance to cytotoxic reagents and are MCE considered to be

critical targets for the eradication of HCC. In this study, we evaluate the effect of a novel compound, TPU0114, on cell growth and CSC features in HCC. TPU0114 is derived from a strain of Streptomyces bacteria with a low 16S rRNA gene identity with other known species. Methods: Huh1 and Huh7 cells were routinely cultured with Dulbecco’s modified eagle medium supplemented with 10% fetal bovine serum. Cell proliferation and tumorigenicity were evaluated using MTS and spheroid formation assays, respectively. Western blotting was used to evaluate the expression of phospho-NF-kB p65 and Bcl-xl. Apoptosis was assessed by Caspase 3 activation and Annexin-V staining. Fluorescence-activated cell sorting was used to evaluate the expression of the CSC markers EpCAM and CD133. Time-lapse imaging was used to monitor cell motility. 5-FU and TPU0114 were obtained from Kyowa Kirin and Bio Technical Research Industry, respectively. Results: Both TPU0114 and 5-FU suppressed the proliferation and motility of Huhl and Huh7 cells at concentrations of 1-10 μg/ml. Interestingly, 5-FU treatment (2.5 μg/ml) resulted in an enrichment of EpCAM+ CD133+ CSCs, whereas TPU0114 treatment (5 μg/ ml) showed no such effect in Huh1 or Huh7 cells. This suggests that TPU0114 may suppress the proliferation of CSCs and non-CSCs equally well. Furthermore, TPU0114 treatment reduced the spheroid-forming capacity of Huh7 cells and increased the number of Annexin-V- and activated Caspase 3-positive cells.

6, p=0.07) and Edmondson grade 3/4 (OR 2.9, p=0.06) to correlate with S1 tumors. Predictive scores were significantly associated with S2 (p<0.001) and S3 (p<0.001) tumors in the validation set, suggesting that the histopathologic features can be used to classify HCC tumors into the 3 subclasses. Gene signatures of Hoshida HCC Subclass S1, cellular hypoxia pathway (which is known to promote lipogenesis), epithelial-mesenchymal transition,

TGF-p activation and oncoprotein YAP signaling were enriched in SH-CC (false discovery rate <0.05). Conclusions: Histopathologic features correlated well with molecular subclasses, and are accompanied with molecular pathway deregulations that potentially contribute to formation of the morphological characteristics. www.selleckchem.com/products/pd-0332991-palbociclib-isethionate.html Multivariable model of histopathologic features may serve as a clinical tool to predict molecular subclass of HCC, which could RG-7388 datasheet inform therapeutic decision in clinic. Disclosures: The following people have nothing to disclose: Poh Seng Tan, Anu Venkatesh, Stephen C. Ward, Claudia

Canasto-Chibuque, Anna Koh, Venugopalan Nair, Manjeet Deshmukh, Shigeki Nakagawa, Xiaochen Sun, Masahiro Kobayashi, Hiromitsu Kumada, Yujin Hoshida Background: Recent evidence suggests that some hepatocellular carcinomas (HCCs) are hierarchically organized, with a subset of cells that possess stem cell features, called cancer stem cells (CSCs). CSCs show chemoresistance to cytotoxic reagents and are MCE considered to be

critical targets for the eradication of HCC. In this study, we evaluate the effect of a novel compound, TPU0114, on cell growth and CSC features in HCC. TPU0114 is derived from a strain of Streptomyces bacteria with a low 16S rRNA gene identity with other known species. Methods: Huh1 and Huh7 cells were routinely cultured with Dulbecco’s modified eagle medium supplemented with 10% fetal bovine serum. Cell proliferation and tumorigenicity were evaluated using MTS and spheroid formation assays, respectively. Western blotting was used to evaluate the expression of phospho-NF-kB p65 and Bcl-xl. Apoptosis was assessed by Caspase 3 activation and Annexin-V staining. Fluorescence-activated cell sorting was used to evaluate the expression of the CSC markers EpCAM and CD133. Time-lapse imaging was used to monitor cell motility. 5-FU and TPU0114 were obtained from Kyowa Kirin and Bio Technical Research Industry, respectively. Results: Both TPU0114 and 5-FU suppressed the proliferation and motility of Huhl and Huh7 cells at concentrations of 1-10 μg/ml. Interestingly, 5-FU treatment (2.5 μg/ml) resulted in an enrichment of EpCAM+ CD133+ CSCs, whereas TPU0114 treatment (5 μg/ ml) showed no such effect in Huh1 or Huh7 cells. This suggests that TPU0114 may suppress the proliferation of CSCs and non-CSCs equally well. Furthermore, TPU0114 treatment reduced the spheroid-forming capacity of Huh7 cells and increased the number of Annexin-V- and activated Caspase 3-positive cells.

2).56 Adiponectin and leptin are 2 such adipocytokines that have been shown to have central and peripheral roles in the regulation of feeding and have been suggested to be altered in migraineurs.26,57,58 Adiponectin.— Adiponectin (ADP) is a protein primarily secreted from adipocytes,

with receptors expressed in the brain (notably in POMC and NPY neurons of the hypothalamus), the endothelium of blood vessels, as well as in liver and muscle.56,59 Human Ceritinib nmr plasma ADP can exist as one of several characteristic oligomers or multimers, including high molecular weight (HMW), middle molecular weight (MMW), or low molecular weight (LMW)-ADP.56,60 It has been noted that women have higher ADP levels than men by puberty.60,61 The ADP is most often reported as having anti-inflammatory properties based on the observations that total-ADP (T-ADP) levels are reduced in obesity

and type II diabetes. However, elevated levels have been noted in type I diabetes, preeclampsia, and arthritis.26 Furthermore, HSP inhibitor several lines of evidence now support adiponectin as exerting either pro- or anti-inflammatory properties depending on the form or multimer involved. For example, the globular head of ADP (gADP) can induce self-tolerance to re-exposure of gADP, as well as tolerance to other pro-inflammatory stimuli,62 suggesting that a pattern similar to what is seen with serotonin in migraineurs, could exist with gADP, ie, low levels of gADP interictally and increases during acute attacks.56 In addition the LMW, multimer of ADP has been shown to have anti-inflammatory properties through reduction of interleukin (IL)-6 secretion, while HMW-ADP has been shown to activate nuclear factor kappa-β (NFkβ) pathways and to induce

IL-6 secretion in humans.63 The first study to evaluate adiponectin and its multimers in headache sufferers found elevated levels of T-ADP in chronic daily headache sufferers, predominantly due to an elevation in the HMW multimer.26 And although episodic migraineurs showed a similar trend with 上海皓元 higher levels of both T-ADP and HMW-ADP as compared with controls, it did not reach significance. Further and larger studies evaluating adiponectin levels both inside and outside an acute migraine attack are needed to evaluate this relationship more fully. Leptin.— Leptin is an adipocytokine with roles in appetite suppression and modulation of inflammatory processes. Like adiponectin, leptin is primarily produced by adipocytes, but also by several other tissues including the brain. In addition, leptin receptors are abundantly expressed in the ARC and DM hypothalamus.64 Leptin is inhibited by testosterone and increased by ovarian sex steroids, with women exhibiting levels that are 2-3 times higher than men even when matched for age and BMI.65,66 Mice with a mutation in the gene encoding leptin (ob/ob mice) or the leptin receptor (db/db mice) express an obese phenotype and have defects in immune function.

2).56 Adiponectin and leptin are 2 such adipocytokines that have been shown to have central and peripheral roles in the regulation of feeding and have been suggested to be altered in migraineurs.26,57,58 Adiponectin.— Adiponectin (ADP) is a protein primarily secreted from adipocytes,

with receptors expressed in the brain (notably in POMC and NPY neurons of the hypothalamus), the endothelium of blood vessels, as well as in liver and muscle.56,59 Human CX-4945 purchase plasma ADP can exist as one of several characteristic oligomers or multimers, including high molecular weight (HMW), middle molecular weight (MMW), or low molecular weight (LMW)-ADP.56,60 It has been noted that women have higher ADP levels than men by puberty.60,61 The ADP is most often reported as having anti-inflammatory properties based on the observations that total-ADP (T-ADP) levels are reduced in obesity

and type II diabetes. However, elevated levels have been noted in type I diabetes, preeclampsia, and arthritis.26 Furthermore, buy LY2109761 several lines of evidence now support adiponectin as exerting either pro- or anti-inflammatory properties depending on the form or multimer involved. For example, the globular head of ADP (gADP) can induce self-tolerance to re-exposure of gADP, as well as tolerance to other pro-inflammatory stimuli,62 suggesting that a pattern similar to what is seen with serotonin in migraineurs, could exist with gADP, ie, low levels of gADP interictally and increases during acute attacks.56 In addition the LMW, multimer of ADP has been shown to have anti-inflammatory properties through reduction of interleukin (IL)-6 secretion, while HMW-ADP has been shown to activate nuclear factor kappa-β (NFkβ) pathways and to induce

IL-6 secretion in humans.63 The first study to evaluate adiponectin and its multimers in headache sufferers found elevated levels of T-ADP in chronic daily headache sufferers, predominantly due to an elevation in the HMW multimer.26 And although episodic migraineurs showed a similar trend with MCE higher levels of both T-ADP and HMW-ADP as compared with controls, it did not reach significance. Further and larger studies evaluating adiponectin levels both inside and outside an acute migraine attack are needed to evaluate this relationship more fully. Leptin.— Leptin is an adipocytokine with roles in appetite suppression and modulation of inflammatory processes. Like adiponectin, leptin is primarily produced by adipocytes, but also by several other tissues including the brain. In addition, leptin receptors are abundantly expressed in the ARC and DM hypothalamus.64 Leptin is inhibited by testosterone and increased by ovarian sex steroids, with women exhibiting levels that are 2-3 times higher than men even when matched for age and BMI.65,66 Mice with a mutation in the gene encoding leptin (ob/ob mice) or the leptin receptor (db/db mice) express an obese phenotype and have defects in immune function.

2).56 Adiponectin and leptin are 2 such adipocytokines that have been shown to have central and peripheral roles in the regulation of feeding and have been suggested to be altered in migraineurs.26,57,58 Adiponectin.— Adiponectin (ADP) is a protein primarily secreted from adipocytes,

with receptors expressed in the brain (notably in POMC and NPY neurons of the hypothalamus), the endothelium of blood vessels, as well as in liver and muscle.56,59 Human www.selleckchem.com/products/cx-4945-silmitasertib.html plasma ADP can exist as one of several characteristic oligomers or multimers, including high molecular weight (HMW), middle molecular weight (MMW), or low molecular weight (LMW)-ADP.56,60 It has been noted that women have higher ADP levels than men by puberty.60,61 The ADP is most often reported as having anti-inflammatory properties based on the observations that total-ADP (T-ADP) levels are reduced in obesity

and type II diabetes. However, elevated levels have been noted in type I diabetes, preeclampsia, and arthritis.26 Furthermore, RG7204 ic50 several lines of evidence now support adiponectin as exerting either pro- or anti-inflammatory properties depending on the form or multimer involved. For example, the globular head of ADP (gADP) can induce self-tolerance to re-exposure of gADP, as well as tolerance to other pro-inflammatory stimuli,62 suggesting that a pattern similar to what is seen with serotonin in migraineurs, could exist with gADP, ie, low levels of gADP interictally and increases during acute attacks.56 In addition the LMW, multimer of ADP has been shown to have anti-inflammatory properties through reduction of interleukin (IL)-6 secretion, while HMW-ADP has been shown to activate nuclear factor kappa-β (NFkβ) pathways and to induce

IL-6 secretion in humans.63 The first study to evaluate adiponectin and its multimers in headache sufferers found elevated levels of T-ADP in chronic daily headache sufferers, predominantly due to an elevation in the HMW multimer.26 And although episodic migraineurs showed a similar trend with 上海皓元医药股份有限公司 higher levels of both T-ADP and HMW-ADP as compared with controls, it did not reach significance. Further and larger studies evaluating adiponectin levels both inside and outside an acute migraine attack are needed to evaluate this relationship more fully. Leptin.— Leptin is an adipocytokine with roles in appetite suppression and modulation of inflammatory processes. Like adiponectin, leptin is primarily produced by adipocytes, but also by several other tissues including the brain. In addition, leptin receptors are abundantly expressed in the ARC and DM hypothalamus.64 Leptin is inhibited by testosterone and increased by ovarian sex steroids, with women exhibiting levels that are 2-3 times higher than men even when matched for age and BMI.65,66 Mice with a mutation in the gene encoding leptin (ob/ob mice) or the leptin receptor (db/db mice) express an obese phenotype and have defects in immune function.

6). Chronic infection with HBV has been recognized to exacerbate liver fibrosis in patients.7-10 Mouse models for liver fibrosis have been successfully established in normal mice31-33 but there was no animal model to mimic liver fibrosis occurring in long-term HBV-infected patients. In this work, to our knowledge, we are the first to observe spontaneously

occurring or CCl4-induced liver fibrosis in HBV-tg mice, and thus explored the possible immunologic selleck mechanisms. The oversensitive liver fibrosis induced by CCl4 in HBV-tg mice may help us to investigate the precise mechanisms of liver fibrosis during chronic HBV infection. A question always exists as to the relationship between liver injury and fibrosis. Although liver injury is not the only pathway involved in liver fibrosis, for example, HSCs might be directly activated without an intermediate step of aggressive liver injury through PDGF overexpression,34 in general, the severity and persistence of liver injury determines the outcome of liver fibrosis. In our study, liver fibrosis followed chronic liver injury. In Fig. 1 we show the spontaneously developed liver fibrosis (increased

transcription of α-SMA, transcription of col1a1, MMP2, and TIMP1) accompanied by liver injury (elevated serum ALT) in 6-month-old selleck kinase inhibitor HBV-tg mice. In Figs. 2-5 it is shown that in chronic CCl4-induced liver fibrosis, HBV-tg mice also had more liver fibrosis associated with more injury. Generally, it was realized that cytotoxic T lymphocytes (CTLs) contribute to initiate hepatocyte injury.35, 36 However,

the effector medchemexpress mechanisms are not only by CTLs but also by other immune cells, among which the roles of innate immune cells in CTL-related or -unrelated inflammatory-mediated fibrosis is unclear and needs study. In CTL-related injury, the CTL-derived cytokines might activate other innate immune cells (such as NKT cells) to produce more inflammatory cytokines, which indirectly lead to hepatocyte injury in addition to CTL direct-killing hepatocytes.37 On the other hand, in CTL-unrelated injury, previously we and others found that innate cells (NK, NKT cells) mediated liver injury in HBV transgenic mice (a mouse model without CTL function).38, 39 In our experiments with respect to HBV-related liver fibrosis, we found NKT cells are pivotal to activate HSCs (Figs. 7, 8). The accumulating data indicate that NKT cells could be activated through TCR recognition (e.g., Vα14/Vβ8 in mice) with antigen-CD1d complex (usually glycolipid) or other killer cell receptors such as NKG2D of NKT cells with their ligands (Rae-1, Mult-1).