We found no effect of liposomal clodronate on HSC viability, thereby excluding the possibility that liposomal clodronate directly induces HSC apoptosis in fibrotic livers (Fig. 2I). We also observed reduced IL-1β and TNF-α mRNA in fibrotic livers from clodronate-treated mice (Fig. 4C). To test the in vivo relevance of this pathway, we first investigated how deficiency of IL-1β, the predominant activator of NF-κB in our coculture experiments, affects liver fibrosis. In contrast to previously published studies, we found no statistically significant difference in BDL-induced liver fibrosis between IL-1R1 knockout and wild-type mice, and further confirmed

this data in the selleck chemicals llc CCl4 and thioacetamide models of liver fibrosis (Supporting Fig. 6). If IL-1 signaling promoted

liver fibrosis by increasing NF-κB–dependent HSC survival rather than direct HSC activation, it would be likely that TNF-α, the other major NF-κB–activating cytokine produced by macrophages, could still achieve NF-κB activation in HSCs and thus compensate for the loss of IL-1 signaling in this model. Based on the hypothesis that absence of both IL-1 and TNF signaling would be required to reduce HSC survival and liver fibrosis, we performed BDL in TNFR1/IL1R1 double knockout mice (dko) and wild-type control mice. Compared with wild-type mice, dko mice showed significantly reduced hepatic fibrosis after 5 or 15 days of BDL (Fig. 5A-B) and a five-fold increase in apoptotic TUNEL and desmin double-positive HSCs without significant differences in hepatic injury (Fig. 5B), supporting HDAC inhibitor our hypothesis that suppression Baricitinib of both IL-1 and TNF signaling are required to affect HSC survival and liver fibrosis. Moreover, we found a significant reduction of NF-κB–dependent genes—including Il6, Cxcl5, Saa3, Serpinb2, and Timp1—in ultrapure unplated HSCs from dko mice, thus confirming that NF-κB activation in HSCs was mediated by TNF

and IL-1 (Fig. 5C). Our microarray analysis revealed an up-regulation of two Trail decoy receptors, murine Trail decoy receptor 1 (Tntrsf23) and murine Trail decoy receptor 2 (Tnfrs22), in HSCs cocultured with HMs and in HSCs from BDL and CCl4 livers (Fig. 5D and Supporting Table 2). Notably, Trail-mediated apoptosis is a major contributor to HSC cell death induced by hepatic natural killer cells in vitro and in vivo.[11, 25] Neutralization of TNF or IL-1 prevented the up-regulation of Tnfrsf22 and Tnfrsf23 mRNA by HMs in coculture experiments (Supporting Fig. 7A). Moreover, depletion of HMs by liposomal clodronate or dko of TNFR1 and IL1R1 reduced Tnfrsf22 and Tnfrsf23 expression in vivo (Supporting Fig. 7B). Liposomal clodronate does not affect HSC number[13] or biology (Fig. 2H,I), but may deplete DCs, a highly endocytotic cell population, as demonstrated by our FACS analysis (Fig. 6A).

We found no effect of liposomal clodronate on HSC viability, thereby excluding the possibility that liposomal clodronate directly induces HSC apoptosis in fibrotic livers (Fig. 2I). We also observed reduced IL-1β and TNF-α mRNA in fibrotic livers from clodronate-treated mice (Fig. 4C). To test the in vivo relevance of this pathway, we first investigated how deficiency of IL-1β, the predominant activator of NF-κB in our coculture experiments, affects liver fibrosis. In contrast to previously published studies, we found no statistically significant difference in BDL-induced liver fibrosis between IL-1R1 knockout and wild-type mice, and further confirmed

this data in the Trichostatin A mouse CCl4 and thioacetamide models of liver fibrosis (Supporting Fig. 6). If IL-1 signaling promoted

liver fibrosis by increasing NF-κB–dependent HSC survival rather than direct HSC activation, it would be likely that TNF-α, the other major NF-κB–activating cytokine produced by macrophages, could still achieve NF-κB activation in HSCs and thus compensate for the loss of IL-1 signaling in this model. Based on the hypothesis that absence of both IL-1 and TNF signaling would be required to reduce HSC survival and liver fibrosis, we performed BDL in TNFR1/IL1R1 double knockout mice (dko) and wild-type control mice. Compared with wild-type mice, dko mice showed significantly reduced hepatic fibrosis after 5 or 15 days of BDL (Fig. 5A-B) and a five-fold increase in apoptotic TUNEL and desmin double-positive HSCs without significant differences in hepatic injury (Fig. 5B), supporting Autophagy activator our hypothesis that suppression Cobimetinib of both IL-1 and TNF signaling are required to affect HSC survival and liver fibrosis. Moreover, we found a significant reduction of NF-κB–dependent genes—including Il6, Cxcl5, Saa3, Serpinb2, and Timp1—in ultrapure unplated HSCs from dko mice, thus confirming that NF-κB activation in HSCs was mediated by TNF

and IL-1 (Fig. 5C). Our microarray analysis revealed an up-regulation of two Trail decoy receptors, murine Trail decoy receptor 1 (Tntrsf23) and murine Trail decoy receptor 2 (Tnfrs22), in HSCs cocultured with HMs and in HSCs from BDL and CCl4 livers (Fig. 5D and Supporting Table 2). Notably, Trail-mediated apoptosis is a major contributor to HSC cell death induced by hepatic natural killer cells in vitro and in vivo.[11, 25] Neutralization of TNF or IL-1 prevented the up-regulation of Tnfrsf22 and Tnfrsf23 mRNA by HMs in coculture experiments (Supporting Fig. 7A). Moreover, depletion of HMs by liposomal clodronate or dko of TNFR1 and IL1R1 reduced Tnfrsf22 and Tnfrsf23 expression in vivo (Supporting Fig. 7B). Liposomal clodronate does not affect HSC number[13] or biology (Fig. 2H,I), but may deplete DCs, a highly endocytotic cell population, as demonstrated by our FACS analysis (Fig. 6A).

The RNA standards targeting the S9 region were obtained by transcription in vitro for generation of a standard curve. The assay developed in this study was found to be 100 LY2109761 in vitro times more sensitive than the conventional RT-PCR for SRBSDV detection. The primers were very specific for SRBSDV. This study clearly demonstrated

the potential usefulness of developed assay for detection and quantitation of SRBSDV in rice samples. Southern rice black-streaked dwarf virus (SRBSDV) is a new species in the genus Fijivirus Group 2 within the family Reoviridae (Zhang et al. 2008; Zhou et al. 2008; Wang et al. 2010), which is transmitted efficiently to rice and maize by the white backed planthopper (WBPH, Sogatella furcifera) in a persistent manner (Pu et al. 2012). Outbreaks of SRBSDV have caused significant crop losses in Southern Asia. In 2009, SRBSDV caused severe losses in North Vietnam, the winter habitat of WBPH (Cuong et al. 2009; Guo et al. 2010), and in China, over 30 million ha of rice field were infected by SRBSDV and 6500 ha of crops failed (Zhou et al. 2010a). In 2010, over 120 million ha of rice were infected by SRBSDV in China, which was 3.5 times more than the previous year, suggesting rapid spread and major

losses in future years (Zhong et al. 2011). SRBSDV isolated was indistinguishable in symptomatology, the shape of virus particles and serological properties from Rice black-streaked dwarf virus check details (RBSDV) and was therefore initially considered to be an isolate of RBSDV (Ruan et al. 1984; Zhou et al. 2004, 2008; Zhang et al. 2008). The pathogen of this disease was not identified until 2008, which was first observed in Yangjiang, Guangdong province in China in 2001 (Zhou et al. 2010a). In order to further study and achieve the ultimate

aim of forecasting and controlling the spread of southern rice black-streaked dwarf disease, the diagnosis of SRBSDV has been improved remarkably with the application of rapid molecular diagnostic systems, such as direct observation of typical symptoms (Zhou et al. 2008), Reverse Transcript-Polymerase Chain Reaction (RT-PCR) (Zhou et al. 2008, 2010b; Ji et al. 2011; Wang et al. 2012a; Dot-Enzyme-Linked Phospholipase D1 Immunosorbent Assay (Dot-ELISA) (Wang et al. 2012b) and Reverse Transcription Loop-Mediated Isothermal Amplification (RT-LAMP) (Zhou et al. 2012). However, some methods are time consuming and inaccurate, and some especially cannot precisely quantify the copy numbers of SRBSDV RNA. The one-step real time RT-PCR assay has many advantages over conventional detection methods, including rapidity, quantitative detection, lower contamination rate, higher sensitivity and specificity. It has already proved to be efficient for the detection of plant RNA and DNA viruses.

8% vs 53.8%), but there was a higher proportion of proximal adenoma in females (36.2% vs 41%) and synchronous adenoma in males (9% vs 5.2%). A total of 206 male and 124 female patients had CRC (Table 5), with males having a higher incidence than females (3.5% vs 2.4%). The distribution pattern was comparable in both sex groups; distal CRC accounted for 56.3% and 57.3% of all the CRC in male and selleck female patients,

respectively; while proximal CRC accounted for 43.2% and 41.1% in male and female patients, respectively. Compared with young patients, elderly patients had a 2.7-fold increase in the incidence of colorectal adenoma (12.9% vs 4.7%). Overall, the distribution pattern was similar in both age groups; for elderly patients, CDK inhibitor the proportion of distal adenoma slightly decreased from 55.9% in young patients (< 50 years) to 54%, while the proportion of

proximal adenoma slightly increased from 37.4% in young patients to 38.1% in elderly patients. The proportion of synchronous adenoma remained relatively static, between 6.7% and 8.4% (Table 6). CRC was observed in 69 young patients and 261 elderly patients, which meant that elderly patients had a 3.1-fold increase in the incidence of CRC. There was a trend towards more proximal CRC in elderly patients (Table 7), although the analysis showed that a shift towards increasing proximal CRC with advanced age was not statistically significant. Traditionally, CRC has been considered a common GI malignancy in Western countries.

However, with the dramatic economic development in China over the past few decades, the incidence of CRC has been steadily increasing. Nevertheless, relatively few epidemiological and clinical CRC studies in Chinese patients have been reported; however, worldwide, 26% of patients with CRC are of Chinese origin. Therefore, it is critical to assess the epidemiology of CRC in the Chinese population. The present study, from a tertiary hospital, finds some interesting trends in colorectal adenoma and CRC in Chinese patients in Shanghai. It was found that there was a non-significant increase in the proportion of left-sided Farnesyltransferase colorectal adenoma and CRC with a non-significant decrease in the proportion of right-sided colorectal adenoma and CRC. Although the present study is not a population-based screening study, it is a study based on the results of a total colonoscopy for more than 10 000 consecutive patients; therefore, we could precisely locate the sites of colorectal adenoma and CRC. In addition, the only investigative method we used was total colonoscopy, so the risk of missing adenoma or CRC by other methods, like double-contrast barium enema or flexible sigmoidoscopy, was greatly reduced. By summarizing the data of 11 025 consecutive patients, this study provides some important information about CRC in our local population; first, the incidence of adenoma and CRC was found to be 9.

The direct effect of type I IFN on CD8+ T cells also occurs in other viral infections.23 Type I IFNs also promote IL-15 production, which is a CD8+ T-cell survival factor24 and plays a critical role in stimulating and maintaining memory CD8+ T cells.23 Type I IFN and IL-12 are also involved in memory CD8+ T-cell development.25 Whether dually functional vector influences HBV-specific CD8+ memory T-cell generation needs further investigation. CD8+ T cells play

a critical role in HBV clearance.3 Intrahepatic HBV-specific CD8+ T cells are required for rapid viral clearance during acute HBV infection. Several HBV-specific CD8+ T-cell cytokines, such as IFN-γ and TNF-α, are essential for suppressing HBV gene expression and replication.3 However, in CHB patients http://www.selleckchem.com/products/MK-2206.html the inhibitory PD-1 receptor is up-regulated on both peripheral blood selleck compound mononuclear cells (PBMCs) and intrahepatic lymphocytes,

particularly on HBV-specific CD8+ T cells, where PD-1 interaction with PD-L1 ligand on APCs results in functional suppression and apoptosis of CD8+ T cells.26 This loss of function is known as “T-cell exhaustion” that is common during persistent viral infection, including human immunodeficiency virus (HIV), HBV, and HCV infection. In the present study, we observed that immunotolerance in chronic HBV-carrier mice correlated with decreased hepatic CD8+ T-cell percentage and number (Fig. 1D), including IFN-γ+ and HBc-specific CD8+ T cells (Fig. 1F,G), as well as higher PD-1

expression (Fig. 1E) and augmented serum TGF-β and IL-10 (Fig. 1C). Treatment with ssRNA-shRNA dually functional vector reversed this immunotolerance. More important, CD8+ T cells were necessary for dual-vector-mediated HBV inhibition (Fig. 6A-C). In addition, NK cells may also be involved in dual-vector-mediated HBV inhibition, for NK cell-depletion partly attenuated dual-vector-mediated HBV suppression (Fig. 5A,B). Increasing data have shown that NK cells play an important role in clearance of HBV, especially Ureohydrolase in the early stage of infection. HBV persistence impairs NK cell function possibly by elevated TGF-β1 through down-regulation of NKG2D/DAP10 and 2B4/SAP expression.27 The dual-vector therapy might release the impairment of NK cell function by both reducing HBV load and arousing activation stimulated by increased type I IFN. The decreased TGF-β1 after dual-vector therapy may also contribute to restoring NK cell function. PRRs play critical roles in defense against invading pathogens by way of recognition of pathogen-associated molecular patterns (PAMPs). Therapeutic strategies that incorporate both PRR activation and target-gene silencing have promising potential to treat cancer and viral infections. Poeck et al.

Several studies have demonstrated the accuracy of CT hepatic angiography (CTHA) in detection of HCC. Our study aims to evaluate the role of CTHA and liver biopsy in this patient group. Methods: A retrospective study of 78 consecutive patients with a first diagnosis of HCC at our institution between January 2008 and May 2014 was performed. Of these, 48 met the inclusion criteria of not meeting European association for study of liver (EASL) guidelines for HCC (Defined as absence of arterial enhancement and portal venous washout). Baseline demographic data was recorded including tumor characteristics,

serum alpha fetoprotein, details Selleck Ibrutinib of radiologic imaging, treatment regime and tumor response using modified response evaluation criteria in solid tumors (mRECIST). Results: There were 48 patients with HCC that had atypical radiological features not fulfilling EASL criteria at initial presentation. The majority were male: 89 % (43/48) with an average age of 66 years (Range 49–84 years). Ultrasound guided biopsy was employed in 45% of cases (22/48), CT hepatic arteriography (CTHA) in 29% (10/48) and conventional angiography in 6% (3/48). No further investigation was performed in 12.5% (6/48) due to poor functional

status and in 14.6% (7/48) treatment was initiated based on enlarging mass and consensus opinion at HCC multidisciplinary meeting. The average diameter of lesions diagnosed using CTHA Sitaxentan was smaller compared with biopsy BTK inhibitor (29 mm (Range: 13–56 mm) vs 56 mm (Range: 13–190 mm) with p = 0.005). The average time to diagnosis of HCC from initial imaging was not significantly different between biopsy

and CTHA : 7 weeks vs 15 weeks (p = 0.13) Of the patients that underwent biopsy for diagnosis 68% (15/22) were treated with complete or partial tumor response seen in 73% (11/15). Of those that underwent CTHA for diagnosis 100% (10/10) were treated achieving a complete or partial tumor response. There was no statistical significance in tumor response rate between the CTHA group compared with biopsy group. Conclusion: CT hepatic angiography provides an alternative to biopsy in the diagnosis of suspected hepatocellular with atypical imaging without the risk of potential tumor seeding associated with biopsy. Smaller lesions can be diagnosed using CTHA and with no adverse difference in time to diagnosis or treatment outcomes. D MANGIRA,1 A CHUANG,2 J CHEN,3 R WOODMAN,4 A WIGG5 1South Australian Liver Transplant Unit, Flinders Drive Bedford Park, Adelaide, 2Flinders University, Bedford Park, SA, Australia Background and Aims: Harmful alcohol drinking impairs long-term survival post liver transplantation (LT). The aim of this study was to investigate the prevalence of harmful relapse to alcohol following LT for alcoholic liver disease (ALD) and to investigate for variables associated with armful relapse, in an Australian LT population.

Several studies have demonstrated the accuracy of CT hepatic angiography (CTHA) in detection of HCC. Our study aims to evaluate the role of CTHA and liver biopsy in this patient group. Methods: A retrospective study of 78 consecutive patients with a first diagnosis of HCC at our institution between January 2008 and May 2014 was performed. Of these, 48 met the inclusion criteria of not meeting European association for study of liver (EASL) guidelines for HCC (Defined as absence of arterial enhancement and portal venous washout). Baseline demographic data was recorded including tumor characteristics,

serum alpha fetoprotein, details RG-7388 concentration of radiologic imaging, treatment regime and tumor response using modified response evaluation criteria in solid tumors (mRECIST). Results: There were 48 patients with HCC that had atypical radiological features not fulfilling EASL criteria at initial presentation. The majority were male: 89 % (43/48) with an average age of 66 years (Range 49–84 years). Ultrasound guided biopsy was employed in 45% of cases (22/48), CT hepatic arteriography (CTHA) in 29% (10/48) and conventional angiography in 6% (3/48). No further investigation was performed in 12.5% (6/48) due to poor functional

status and in 14.6% (7/48) treatment was initiated based on enlarging mass and consensus opinion at HCC multidisciplinary meeting. The average diameter of lesions diagnosed using CTHA Fossariinae was smaller compared with biopsy Pexidartinib (29 mm (Range: 13–56 mm) vs 56 mm (Range: 13–190 mm) with p = 0.005). The average time to diagnosis of HCC from initial imaging was not significantly different between biopsy

and CTHA : 7 weeks vs 15 weeks (p = 0.13) Of the patients that underwent biopsy for diagnosis 68% (15/22) were treated with complete or partial tumor response seen in 73% (11/15). Of those that underwent CTHA for diagnosis 100% (10/10) were treated achieving a complete or partial tumor response. There was no statistical significance in tumor response rate between the CTHA group compared with biopsy group. Conclusion: CT hepatic angiography provides an alternative to biopsy in the diagnosis of suspected hepatocellular with atypical imaging without the risk of potential tumor seeding associated with biopsy. Smaller lesions can be diagnosed using CTHA and with no adverse difference in time to diagnosis or treatment outcomes. D MANGIRA,1 A CHUANG,2 J CHEN,3 R WOODMAN,4 A WIGG5 1South Australian Liver Transplant Unit, Flinders Drive Bedford Park, Adelaide, 2Flinders University, Bedford Park, SA, Australia Background and Aims: Harmful alcohol drinking impairs long-term survival post liver transplantation (LT). The aim of this study was to investigate the prevalence of harmful relapse to alcohol following LT for alcoholic liver disease (ALD) and to investigate for variables associated with armful relapse, in an Australian LT population.

Disclosures: The following people have nothing to disclose: Abdelrahman Zekri, Hosny M. Salama, Abeer Bahnassy, Shereen M. Al Alim, Ola Ahmed, Mai Lotfy, Eman Medhat, Rasha Ahmed, Sherief Musa Mesenchymal stem cells (MSC) display a striking immunoregulatory property. This property has been used in several clinical settings; particularly, MSC infusion could resolve severe, acute graft-vs-host disease. learn more Most of the data

suggest that this property involves secretion of specific cytokines and mechanisms mediated by cell-cell contact. In addition, MSC are also likely to modulate the differentiation and function of dendritic cells (DC). However, the underlying mechanisms are still poorly understood. In this study, we found that human MSC from umbilical cord (huc-MSC) induced immature dendritic cells (iDC) to differentiate into

a novel tolerogenic DC subset (MSC-DC) with a stable phenotype and function when cocultured. MSC-DC display the low immunogenicity and immune tolerance by triggering a T helper type 2-polarizing program and down-regulating the pro-inflammatory factor production. Further study demonstrates that huc-MSC induce the tolerogenic MSC-DC generation through the IL-6/STAT3/SOCS1/TLR4 signaling network. Huc-MSC induced the higher expression of SOCS1 in MSC-DC, which were activated by secreting a larger number of IL-6 through the JAK-STAT pathway, repressing toll like receptor 4 (TLR4) Epigenetics inhibitor signaling pathway, and ultimately inducing the generation of novel tolerogenic dendritic cells. Moreover, Huc-MSC could increase phophorylation of Akt, but inhibit phophorylation of IRF3. We also observed that amount of microRNAs changed when cocultured. We found that miR-378 was an important factor in the generation of novel tolerogenic

dendritic cells by targeting STAM2. These results indicate that microRNAs could play essential roles in the production of the tolerogenic MSC-DC. Taken together, our data proposed a new Non-specific serine/threonine protein kinase molecular mechanism of MSC in regulating tolerogenic DC production and promote the clinical application of MSC in new and broader immune applications, including treatment of allograft rejection and graft-vs-host disease in organ transplantation and autoimmune liver diseases. Disclosures: The following people have nothing to disclose: Guo-Ying Wang, Yi-nan Deng, Yong Zou, Minru Li, Qi Zhang, Gui-Hua Chen Bioengineering of a fully functional tissue reguires precise recapitulate normal tissue development. Specifically for the liver, one may use bipotent human liver progenitor cells (hFLCs) capable of differentiation into hepatocytes and cholangiocytes.

Disclosures: The following people have nothing to disclose: Abdelrahman Zekri, Hosny M. Salama, Abeer Bahnassy, Shereen M. Al Alim, Ola Ahmed, Mai Lotfy, Eman Medhat, Rasha Ahmed, Sherief Musa Mesenchymal stem cells (MSC) display a striking immunoregulatory property. This property has been used in several clinical settings; particularly, MSC infusion could resolve severe, acute graft-vs-host disease. ATM/ATR phosphorylation Most of the data

suggest that this property involves secretion of specific cytokines and mechanisms mediated by cell-cell contact. In addition, MSC are also likely to modulate the differentiation and function of dendritic cells (DC). However, the underlying mechanisms are still poorly understood. In this study, we found that human MSC from umbilical cord (huc-MSC) induced immature dendritic cells (iDC) to differentiate into

a novel tolerogenic DC subset (MSC-DC) with a stable phenotype and function when cocultured. MSC-DC display the low immunogenicity and immune tolerance by triggering a T helper type 2-polarizing program and down-regulating the pro-inflammatory factor production. Further study demonstrates that huc-MSC induce the tolerogenic MSC-DC generation through the IL-6/STAT3/SOCS1/TLR4 signaling network. Huc-MSC induced the higher expression of SOCS1 in MSC-DC, which were activated by secreting a larger number of IL-6 through the JAK-STAT pathway, repressing toll like receptor 4 (TLR4) Palbociclib datasheet signaling pathway, and ultimately inducing the generation of novel tolerogenic dendritic cells. Moreover, Huc-MSC could increase phophorylation of Akt, but inhibit phophorylation of IRF3. We also observed that amount of microRNAs changed when cocultured. We found that miR-378 was an important factor in the generation of novel tolerogenic

dendritic cells by targeting STAM2. These results indicate that microRNAs could play essential roles in the production of the tolerogenic MSC-DC. Taken together, our data proposed a new Fludarabine clinical trial molecular mechanism of MSC in regulating tolerogenic DC production and promote the clinical application of MSC in new and broader immune applications, including treatment of allograft rejection and graft-vs-host disease in organ transplantation and autoimmune liver diseases. Disclosures: The following people have nothing to disclose: Guo-Ying Wang, Yi-nan Deng, Yong Zou, Minru Li, Qi Zhang, Gui-Hua Chen Bioengineering of a fully functional tissue reguires precise recapitulate normal tissue development. Specifically for the liver, one may use bipotent human liver progenitor cells (hFLCs) capable of differentiation into hepatocytes and cholangiocytes.

In both Ath-fed

Wt and foz/foz mice with NASH, Tlrs-4, 7, 9 transcripts increased, with similar pattern for TLR4 and 9 proteins. In Ath-fed Tlr9−/− mice, liver necro-inflammatory score and fibrosis markers were substantially diminished compared with Wt, despite similar steatosis and hepatic lipid levels. Likewise, Ath feeding failed to increase NF-κB and c-Jun activation, macrophage/neutrophil infiltration and pro-inflammatory Th1 cytokines selleck products in Tlr9−/− mice compared to major increases in Wt. Conversely, expression of anti-inflammatory Th2 cytokines (IL-4, IL-10) was not different. Despite less inflammation in Ath-fed Tlr9−/− vs Wt mice, hepatocyte damage (serum ALT, high mobility group box 1 [HMGB-1], CK-18, asialoglycoprotein [ASGPR] levels) and circulating endotoxin levels were higher. We interpret these changes as reflecting

enhanced necrosis (and/or necroptosis) in response to endotoxemia; correspondingly, this website livers showed increased RIP3 (necrosis marker) and MLKL (necroptosis) expression. Further, Tlr9−/− hepatocytes were more susceptible to palmitic acid and endotoxin-induced injury than Wt. Using BM chimeras, we showed that TLR9 in BM-derived myeloid cells and not hepatocytes at least partially mediates Ath diet-induced hepatic injury. This is supported by our observation that, compared to Wt, Tlr9−/− BM-derived macrophages are resistant to activation by CpG DNA, necrotic mediators and LPS induced M1 polarization to produce pro-inflammatory cytokines. Conclusion: These novel data in human liver, in mice with metabolic syndrome-related NASH and with the atherogenic dietary model of NAFLD indicate that TLR9 activation is a critical pro-inflammatory trigger in NASH that is likely mediated via macrophages. In addition, Arachidonate 15-lipoxygenase however, TLR9 appears to confer hepatocyte protection in NASH as TLR9-deleted cells are more susceptible to lipotoxicity and endotoxin-induced necrosis. If this is correct, TLR9 blockade may not be an attractive therapeutic approach in NASH because, while it could dampen macrophage activation, it could also abrogate an intrinsic hepatoprotective pathway against

lipotoxic molecules and gut-derived pathogen-associated molecular patterns. B ALZAHRANI,1,2 J GEORGE,1,2 L HEBBARD1,2 1Storr Liver Unit, Westmead Millennium Institute, PO Box 412, Darcy Road, Westmead, NSW 2145, Australia, 2Sydney Medical School, University of Sydney, NSW, Australia Introduction: Liver fibrosis is the scarring process that represents the liver’s response to injury. Adiponectin has been shown to have an important role in the regulation of fibrosis, as adiponectin null mice have greater levels after carbon tetrachloride (CCl4) treatment. Adiponectin binds to three receptors: AdipoR1, AdipoR2 and T-cadherin. Our unpublished studies suggest that AdipoR1 and AdipoR2 null mice have unchanged fibrosis after CCl4 treatment. The role of T-cadherin in hepatic biology is unknown.