Human immunodeficiency virus (HIV-1) has been reported to inhibit the maturation of DC, but a clear link between maturation and function has not been elucidated. To understand further the effects of HIV-1 on DC maturation and function, we expanded upon previous investigations and assessed the effects of HIV-1 infection on the expression of surface molecules, carbohydrate endocytosis, antigen presentation and lipopolysaccharide (LPS) responsiveness over the course of

maturation. In vitro infection with HIV-1 resulted in an increase in the expression of DC-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN) as well as decreases in maturation-induced CCR7 and major histocompatibility complex Doxorubicin price (MHC)-II expression. Retention of endocytosis that normally occurs with DC maturation as well as inhibition of antigen presentation to CD8+ T cells was also observed. Mitogen-activated protein kinase (MAPK) responsiveness to LPS as measured by phosphorylation of p38, c-Jun N-terminal kinase (JNK) and extracellular-regulated kinase (ERK)1/2 was not affected by HIV-1 infection. In summary, in-vitro HIV-1 impairs PI3K Inhibitor Library DC maturation, as defined by cell surface protein

expression, with selective alterations in mature DC function. Understanding the mechanisms of DC dysfunction in HIV infection will provide further insight into HIV immune pathogenesis. Dendritic cells (DC) are critical mediators of the interaction between the adaptive and innate immune systems and are responsible for the presentation of antigens and co-stimulatory molecules to naive T cells in the secondary lymph organs [1]. When not presenting antigens in the secondary lymph organs, DC are located throughout the body in tissues in an immature form, where they constantly ‘sample’ their environment

for pathogens through pattern recognition receptors [2]. During normal maturation, DC change from antigen capture Sclareol cells to antigen-presenting cells [3]. Maturation is characterized by a decrease in phagocytic and pinocytic activities [3] and decreases in the expression of cell surface molecules associated with those functions, including mannose receptors, CD14 and C-type lectin receptors such as DC-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN) [4–6]. These changes are accompanied by concomitant increases in the expression of surface molecules that facilitate antigen presentation and adaptive immune system activation such as CD80, CD86, CD40, major histocompatibility complex (MHC)-I and MHC-II [7–11]. Additionally, expression of the immunoregulatory surface molecule CD83 increases when DC mature and this is accompanied by decreases in the expression of the chemokine receptor CCR5 and increases in CCR7 expression [12–14].

So far, three other inflammasome prototypes have been described: the NALP1

inflammasome, the IL-1β converting enzyme protease-activating factor (IPAF) inflammasome and recently the absent in melanoma 2 (AIM2) inflammasome.6 To date, much attention has focused around the inflammatory properties of ASC; however, recent evidence has highlighted the importance of ASC in adaptive immune responses. Studies using ASC−/− mice have Angiogenesis inhibitor revealed its significance in adaptive immunity in several physiological and pathological situations. It seems that ASC is essential to mount protective T-cell and B-cell immunity against influenza virus infection.7 Expression of ASC on dendritic cells (DCs) has also been described as being critical in T-cell priming and the subsequent induction of both antigen-specific cellular and humoral immunity and on the onset of collagen-induced arthritis.8 Furthermore, ASC has also been strongly linked to modulating joint inflammation

in antigen-induced arthritis by affecting the induction of antigen-specific cellular immunity.9 Finally, ASC has been shown to contribute to disease progression in experimental autoimmune encephalomyelitis.10 However, the cellular and molecular basis behind the importance of ASC in adaptive immunity remains largely unexplored. We have previously described how ASC−/− T cells exhibit impaired proliferative capacity in response to both antigen-specific and non-specific (anti-CD3/CD28) stimulation ex learn more vivo.9 In this study we explored the cellular basis for the influence of ASC on T-cell proliferation and subsequent diglyceride effector function. ASC−/− mice1 and NALP3−/− mice11 were backcrossed into the C57BL/6 background for at least nine generations and were compared with wild-type (WT) littermates in this study. Mice were bred under conventional, non-specific pathogen-free conditions. Mice between 8 and

12 weeks of age were used for experiments. All experiments were carried out in agreement with Institutional and Swiss regulations. CD3+ T cells were enriched from splenocyte suspensions by negative selection using the EasySep mouse T-cell enrichment kit (StemCell Technologies, Grenoble, France). Splenic CD4+ and CD8+ T-cell fractions were purified using magnetic antibody cell sorting CD4+ and CD8+ MicroBeads, respectively (> 95%) (Miltenyi Biotec, Bergisch Glaabach, Germany). T cells (2 × 105/200 μl per well) were cultured in 96-well plates previously coated with anti-mouse CD3 (2 μg/ml, clone 145-2C11; eBioscience, San Diego, CA) and anti-CD28 (2 μg/ml, clone 37-51; eBioscience). For co-culture experiments, different isolated T-cell fractions were plated in 96-well plates at a 1 : 1 ratio (1 × 105 T cells per fraction in 200 μl).

To this end, the authors depleted the siRNA pathway Dicer protein, Dicer-2, as well as the miRNA biogenesis factors Drosha and Dicer-1 from shrimp, and then challenged the shrimp with WSSV. While the levels of vp28-siRNA were unaffected in Drosha- and Dicer-1-depleted animals, knockdown of Dicer-2 abolished vp28-siRNA accumulation. The authors also detected vp28-siRNA in the cytoplasm of wild type infected cells using RNA-FISH, but not in Dicer-2-depleted animals. Therefore, the siRNA pathway component Dicer-2, but not

the miRNA pathway components Drosha or Dicer-1, is required for vp28-siRNA biogenesis in WSSV-infected shrimp. To investigate Selleck CHIR-99021 whether the vsiRNA functions in the Bortezomib solubility dmso context of RISC, Huang and Zhang [20] used an electrophoretic mobility shift assay to demonstrate that synthetic vp28-siRNA interacts with Ago2, but not Ago1, while a control siRNA specifically interacts with Ago1 rather than Ago2. These results suggest that vp28-siRNAs produced during infection are incorporated into an Ago2-containing RISC. However, additional studies, such as immunoprecipitation and sequencing of Ago2-bound small RNAs from infected shrimp, are necessary

to verify this conclusion. It will be essential to determine whether depletion of Ago2 renders shrimp more susceptible to virus infection, since this would demonstrate a role for both the biogenesis and effector steps of the RNAi pathway in antiviral defense. Arguably the most important discovery of Huang and Zhang [20] is their finding that Dicer-2 is required for antiviral defense against WSSV. Depletion of either Dicer-2 or its product, vp28-siRNA, rendered the shrimp more susceptible to WSSV infection, as evidenced by the replication of WSSV being enhanced more than tenfold at 24 and 48 h postinfection in these animals. These results clearly implicate the biogenesis step of the shrimp RNAi pathway in suppressing DNA viral infection in vivo. The work of Huang and Zhang [20] raises several important

questions that will likely guide acetylcholine future efforts to characterize anti-viral responses against DNA viruses. Regarding the biogenesis of vsiRNAs, it is clear that one particular vsiRNA, vp28-siRNA, is generated during WSSV infection, and that it is potently anti-viral. How can one particular vsiRNA provide so much protection? Are other vsiRNAs produced during infection? What are the viral precursors that give rise to these small RNAs? Moreover, how do dsDNA viruses differ from RNA viruses in their recognition and processing by the cell? As mentioned previously, in insects, DNA virus-derived siRNAs can be produced from bidirectional transcription [15] or from structured single-stranded RNAs [16] (Fig. 1A).

[37, 40, 42] Superficial infections can occur in patients suffering from an immunosuppressive disorder, such as leukaemia or HIV, but also in premature infants and apparently healthy adult persons.[42, 45-52] They are characterised by rapidly developing extensive tissue necrosis leading to purple to black discolouration of the skin.[45, 53] In individual cases Angiogenesis inhibitor involvement

of deeper tissue, leading to necrotising fasciitis and cellulitis, has also been reported.[40, 46, 54] In the most severe cases, cutaneous infections can progress to disseminated disease, especially in immunocompromised patients and premature infants.[47, 55] In premature infants, Lichtheimia infections furthermore commonly affect the gastrointestinal tract,[56] often resembling necrotising enterocolitis.[57] Since most studies on mucormycosis do not examine the type of infection on a species-specific level, it is hard to assess the incidence of

different types of infections for Lichtheimia. Only two studies include more detailed information about infections with Lichtheimia species. The study of Alvarez et al. included seven cases of Lichtheimia infections with pulmonary infection and infections of the sinuses as the most important presentations (6 of 7 cases).[22] Only one additional study focused on species-specific analysis of healthcare-associated mucormycosis. Cutaneous and pulmonary infections MAPK inhibitor were the most common types of infection representing 70% and 20% respectively.[83] However, due to the limitations of the currently available studies, e.g. low numbers of cases Ergoloid or restriction to a special patient group, no clear conclusions can be drawn about the incidence of the different types of infections and underlying conditions for the development of Lichtheimia infections. In addition to causing infections, Lichtheimia species have been implicated in the form of occupational hypersensitivity pneumonitis termed Farmer’s lung disease (FLD). Farmer’s lung disease is caused by recurrent exposure to certain microorganisms, especially

in farming personnel. The acute form is characterised by influenza-like symptoms like sweating, chills, fever, nausea and headache. The (sub)chronic form is associated with coughing and dyspnoea for up to several weeks.[58] As mentioned above, Lichtheimia species represent a major contaminant of farming material like hay and straw. The occurrence of FLD has been associated with increased numbers of L. corymbifera in the farm environment and L. corymbifera-specific antibodies in affected patients.[59] Furthermore, in vitro experiments with lung epithelial cells revealed high expression of pro-inflammatory and allergic mediators (IL-8, IL-13) after exposure to extracts of L. corymbifera.[60] These results support the role of Lichtheimia in the development of hypersensitivity pneumonia.

1a). During the late dry season, bush savanna associated with finer-grained sandstone became most strongly favoured, along with increased use of C. mopane tree savanna on shale and mudstone, particularly in the wetter of the 2 years. Zebra strongly favoured the open bush savanna associated with basaltic soils, the most widely prevalent vegetation type, throughout the year (Fig. 1b). Buffalo showed a broadly distributed use of habitat

types during the wet season, but concentrated strongly in the granitic region near the river during the dry season, most especially in the drier year (Fig. 1c). Both sable and zebra foraged mainly in upland regions of the landscape throughout the dry season (Fig. 2a). Buffalo concentrated in slope regions in the early dry season and made greater use of lowland near the river during the late dry season. Sable and zebra entered this lowland only to drink from pools in the river. SCH772984 clinical trial The foraging areas of GSK2126458 zebra were usually more open with shorter trees than those occupied by sable (Fig. 2b). However, tree canopy cover and height in the foraging areas of buffalo were very similar to those for sable. Grass height

in foraging areas was generally in the range 41–80 cm for all three grazers, with no seasonal variation (Fig. 2c). The grassland tended to be greener than in the foraging areas of sable than in those of zebra and buffalo in the early dry season, but this distinction fell away during the late dry season when very little green grass remained (Fig. 2d). The model incorporating both grass greenness

and tree canopy cover best distinguished the foraging areas of sable from those zebra, although the model with greenness replaced by season was almost equally supported (Table 1a). For the sable–buffalo comparison, the best supported model included only grass greenness as a distinguishing feature, but with some support for an interaction with season (Table 1b). Either tree cover or topography was the most strongly supported distinction between the foraging areas of zebra and buffalo (Table 1c). Acceptance of the grass at feeding sites was more strongly influenced by grass greenness for sable than was the case for both zebra (G2 = 91.6, d.f. = 3, P < 0.001) and buffalo others (G2 = 116.0, d.f. = 3, P < 0.001) (Fig. 3a). Zebra appeared somewhat indifferent to distinctions in greenness in their grass acceptance throughout the dry season, while buffalo showed an inconsistent response to grass greenness in the early dry season, and foraged solely in sites containing little or no green grass during the late dry season. During the late dry season, sites containing grass that was more than 10% green were present only in the feeding sites of sable. Sable differed from both zebra (G2 = 94.08, d.f. = 2, P < 0.001) and buffalo (G2 = 43.96, d.f. = 2, P < 0.001) in the influence of grass height on acceptance.

Conclusion: Anchoring IFNα to ApoA-I prolongs the half-life of IFNα and promotes targeting to the liver. Importantly, the fusion protein shows increased immunostimulatory properties this website and lower hematological toxicity. (HEPATOLOGY 2011;) Interferon alpha (IFNα)

is a key component of the innate immune system and plays an essential role in the defense against viral infections. In addition to direct antiviral effects,1 IFNα displays antiproliferative,2 proapoptotic,3 immunomodulatory,4 and antifibrogenic activities.5 Recombinant IFNα is widely employed for the treatment of chronic viral hepatitis and neoplastic diseases6, 7 but a number of side effects limit its use. Alterations in the hematopoietic system, mainly thrombocytopenia and leukopenia, are among the most important unwanted consequences of this therapy. As a result, IFNα is not indicated in patients with low platelet or leukocyte counts, which is the case with many subjects with advanced chronic viral infection.8 Another limitation of IFNα-based therapies is its short half-life in plasma. The therapeutic activity of IFNα in chronic viral hepatitis is enhanced

by formulations that prolong its persistence in the circulation, selleck compound including pegylation of the molecule (PEG-IFNα)9 or its fusion with stabilizing proteins such as albumin.10 BCKDHA However, these modifications of the IFNα molecule do not provide

hepatic tropism, a property that would be desirable in the treatment of liver diseases such as chronic viral hepatitis. We therefore designed an IFNα fusion protein that combines both increased half-life and liver tropism. We selected apolipoprotein A-I (ApoA-I), the main protein component of high-density lipoproteins (HDLs), as the stabilizing and targeting moiety. HDLs are generated in the liver and remove cholesterol from peripheral tissues for delivery to hepatocytes.11 Consistent with the key role of HDLs in the reverse cholesterol transport, it has been shown that ApoA-I accumulates preferentially in the liver following its systemic administration.16 Scavenger receptor class B type I (SR-BI) plays a crucial role in HDL biology.13 After binding to SR-BI, HDLs mediate the uptake of cholesteryl esters and phospholipids from the cells and promote cytoprotective functions by imperfectly understood mechanisms involving multiple interactions between HDLs (lipid or protein moiety) and cell surface receptors.14 SR-BI is expressed at low levels in a wide variety of cells, and at high levels in the liver, adrenal glands, ovaries, testis, intestinal cells, phagocytes, and endothelial cells.11, 15 The present work evaluates the properties of a new fusion protein designed to increase the half-life of IFNα and to target the liver.

2. The peripheral blood Th1, Th17 cell numbers are remarkable higher in IBD patients, which suggests that there are important relations on the changes of proportion of Th1 and Th17 cells with IBD pathogenesis and progression. Key Word(s): 1. IBD; 2. MDSC; 3. Th1 cells; 4. Th17 cells; Presenting Author: CHENWEI CHANG Additional Authors: LIYUE QIN, GAO NAN, ZHANGGUANG BO Corresponding Author: CHENWEI CHANG Affiliations: Department of Gastroenterology. Objective: To tentative approach to the therapeutic effects and mechanisms of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] against DSS (dextran sulfate sodium)-induced ulcerative colitis (UC) in mice. Methods: Thirty

BALB/c mice were randomly assigned small molecule library screening into five groups: group A (control group, n = 6), group B (model group, n = 6), group C (low-dose intervention group, n = 6), group D (moderate-dose intervention group, n = 6), group E (large-dose intervention group, n = 6). drinking 5% DSS solution for seven days in groups B, C, D, E were induced UC model, while group A was given equal volume of distilled water. As to start of the DSS exposure, groups C, D, E were intraperitoneally injected on 1, 3, 5, and 7 days to each mouse with low dose (50 ng), medium dose (100 ng), high-dose (200 ng) of 1,25(OH)2D3, respectively. While group A, B were intraperitoneally injected with sterile soybean oil soluble drug

carrier. On 8 days after molding, all mice were executed. The disease activity index (DAI) in mice were estimated by selleck general

observation and histopathological score (HPS) were calculated by routine pathologic examination. The expressions of IFN-γmRNA, IL-17 mRNA and IL-21 mRNA in distal colon, and IFN-γ, IL-17 and IL-21 of spleen lymphocytes of mice were measured by RT-PCR or by flow cytometry, and the protein expression of IFN-γ, IL-17 and IL-21 in distal colon of mice were measured by immunohistochemistry. Results: (1) The DAI heptaminol and HPS in the model group (B group) were significantly higher than in group A (7.33 ± 1.03 vs 0.33 ± 0.52, 12.00 ± 0.63 vs 0.17 ± 0.41, P < 0.01). The DAI (2.83 ± 0.40, 2.83 ± 0.75, 2.33 ± 0.52, respectively) and HPS (10.83 ± 0.98, 7.50 ± 0.84, 6.67 ± 0.52, respectively) in the three intervention groups were significantly decreased than in group B (P < 0.01). (2) The expressions of IFN-γmRNA, IL-17mRNA and IL-21mRNA in group B (3.11 ± 0.24, 1.38 ± 0.38, 3.32 ± 0.16, respectively) were significantly higher than in group A (1.38 ± 0.16, 0.52 ± 0.15, 1.47 ± 0.19, respectively)(P < 0.01), and were significantly lower in group C (2.48 ± 0.21, 0.75 ± 0.14, 0.72 ± 0.19, respectively), group D (2.02 ± 0.22, 0.56 ± 0.16, 0.73 ± 0.16, respectively), group E (2.00 ± 0.20, 0.53 ± 0.19, 0.76 ± 0.09, respectively) (P < 0.01). The expressions of IFN-γ, IL-17 of spleen lymphocytes in mice were significantly higher in group B [(58.98 ± 3.

Theoretically, earlier cardiac transplantation may be beneficial, given that the hemodynamic improvement with additional cardiac surgeries Selleck AZD6244 is often limited. Furthermore, each additional surgery is associated with higher transfusion requirements with negative implications for future transplants and may increase the

complexity of cardiac transplantation. We anticipate that the hepatologist will play a central role in the multidisciplinary management of these complex patients. It is hoped that the formation of consortia may allow for better elucidation of the nature and frequency of complications as well as clarification of the optimal management in this vulnerable population. “
“Alteration of cell surface proteolysis has been proposed to play a role in liver fibrosis, a grave complication of biliary atresia (BA). In this study we investigated the roles of hepatocyte growth factor activator inhibitor (HAI)-1 and -2 in the progression of BA. The expression levels of HAI-1 and -2 were significantly increased in BA livers compared with those in neonatal hepatitis and correlated with disease progression. In BA livers, HAI-1 and -2 were coexpressed in cells involved in ductular DMXAA clinical trial reactions. In other selective cholangiopathies,

ductular cells positive for HAI-1 or HAI-2 also increased in number. Inflammatory cytokines, growth factors, and bile acids differentially up-regulated expression of HAI-1 and -2 transcripts in fetal liver cells and this induction could be antagonized by a cyclooxygenase-2 inhibitor. Conditioned media from cell PKC inhibitor lines stably overexpressing HAI-1 or HAI-2 enhanced the fibrogenic activity of portal fibroblasts and stellate cells, suggesting that both proteins might be involved in liver fibrosis. Because HAI-1 and -2 colocalized in ductular reactions sharing similar features to those observed during normal liver development, we sought to investigate the role of HAI-1 and -2 in cholangiopathies by exploring their functions in fetal liver cells.

Knockdown of HAI-1 or HAI-2 promoted bidirectional differentiation of hepatoblast-derived cells. In addition, we showed that the hepatocyte growth factor activator, mitogen-activated protein kinase kinase 1, and phosphatidylinositol 3-kinase signaling pathways were involved in hepatic differentiation enhanced by HAI-2 knockdown. Conclusion: HAI-1 and -2 are overexpressed in the liver in cholangiopathies with ductular reactions and are possibly involved in liver fibrosis and hepatic differentiation; they could be investigated as disease markers and potential therapeutic targets. (Hepatology 2012) Biliary atresia (BA) is one of the most important causes of hepatic fibrosis in children.1 Liver fibrosis is a complex process that involves extensive extracellular matrix (ECM) remodeling and proteolysis.2 Using microarray analysis, Chen et al.

Key Word(s): 1. STAT3; 2. Snail; 3. SGC7901;

4. vector constuction; Presenting Author: SHANSHAN SHEN Additional Authors: XIAOPING ZOU Corresponding Author: XIAOPING ZOU Affiliations: Nanjing Drum Tower Hospital Objective: The oxidative stress plays an essential role in carcinogenesis and progression click here of colorectal cancer through many mechanisms, in which NF-κB (nuclear factor kappa B) signaling pathway is particularly involved. ABCG2 (ATP-Binding Cassette Family G2 Transporters) is an ABC (ATP-binding cassette) transporter. Previously, many studies in colorectal caner have focused on its relevance to multidrug resistance, however, other functions of ABCG2 remains largely unexplored. Our previous study for the first time demonstrated that the ABCG2 is capable of protecting HEK293 cells (human embryonic kidney epithelial cells 293) from ROS (Reactive oxygen species)-mediated cell damage and death. In normal circumstances, ABCG2 protect gastrointestinal epithelium cells from toxins and loss of ABCG2 in local intestinal tract might lead to the carcinogenesis of colorectal cancer. Since ABCG2 and oxidative stress is cloesly related to bilogical characteristics of colorectal cancer, we hypothesize that ABCG2 may reduce oxdative stress and inhibit the malignant behaviour of colorectal cancer. NF-κB

signaling pathway may be involved in the Gefitinib effects of ABCG2. Methods: Immunohistochemistry (IHC) was applied to examine the protein expression of ABCG2 and NF-κB in 21 colorectal carcinoma specimens and 21 normal colorectal epithelial specimens from Drum Tower Hospital Affiliated to Medical School of Nanjing University. RT-PCR and Western blot were used to test the ABCG2 expression level in four different colorectal cancer cell lines (LoVo, HT-29, Caco-2, Sw480) and LoVo cells which were confirmed to have no ABCG2 expression were selected to do

the following ABCG2 overexpressing experiments. The construction and cloning of ABCG2-pEGFP-C1 Urease recombinant plasmid were followed the manufacturer’s protocols and the recombinant plasmid was identified by restriction enzyme test and sequencing. The expression of cloned ABCG2 in transfected LoVo cells transient transfected with Lipofectamine 2000 was examined by Western blotting and Immunocytochemistry. The effects of ABCG2 on the ROS production induced by hydrogen peroxide (H2O2) were monitored by ROS assay. The effects of ABCG2 on the viability of H2O2-treated cells were measured using propidium iodide (PI) assay following manufacturer’s instructions. All the data were analyzed with SPSS 16.0 statistical software package. The comparison between two samples was analyzed by Student t-test and multiple samples were compared by one-way ANOVA.

Our experimental data showed that treatment with ATZ significantly enhanced LPS/D-Gal-induced elevation of serum aspartate transaminase (AST) and alanine transaminase (ALT), exacerbated the hepatic histopathological abnormality and decreased the survival rate of experimental animals. ATZ inhibited the activity of CAT, increased the content of H2O2 and the levels of malondialdehyde

Bortezomib chemical structure (MDA) in liver tissues. In addition, treatment with ATZ also enhanced LPS/D-Gal-induced hepatic apoptosis as evidenced by increased caspases activities in liver tissues and increased number of terminal deoxynucleotidyl transferase dUTP nick end labeling positive cells in liver sections. These findings suggested that CAT might be involved in the progression of LPS/D-Gal-induced fulminant liver injury. “
“Hepatic ischemia/reperfusion (IRI) injury remains a major challenge in clinical Palbociclib ic50 orthotopic liver transplantation (OLT). Tenascin-C (Tnc) is an extracellular matrix protein (ECM) involved in various aspects of immunity and tissue injury. Using a Tnc-deficient mouse model, we present data that suggest an active role for Tnc in liver IRI. We show that Tnc-deficient mice have a reduction in liver damage and a significant improvement in liver regeneration after IRI. The inability

of Tnc−/− mice to express Tnc significantly reduced the levels of active caspase-3/transferase-mediated dUTP nick end-labeling (TUNEL) apoptotic markers and enhanced the expression of the proliferation cell nuclear antigen (PCNA) after liver IRI. The lack of Tnc expression resulted in impaired leukocyte recruitment and decreased expressions of interleukin (IL)-1β, IL-6, and CXCL2 after liver reperfusion. Tnc-deficient livers were characterized by altered expression patterns of vascular adhesion molecules, such as vascular cell adhesion molecule-1 and platelet endothelial cell adhesion molecule-1 post-IRI. Moreover, matrix metalloproteinase-9 (MMP-9) synthesis, which

facilitates leukocyte transmigration across vascular barriers in liver IRI, was markedly down-regulated in the absence of Tnc. We also show that Tnc is capable of inducing MMP-9 expression in isolated neutrophils through Toll-like receptor 4. Therefore, our data suggest that Tnc is a relevant mediator of the pathogenic events underlying out liver IRI. The data also support the view that studies aimed at further understanding how newly synthesized ECM molecules, such as Tnc, participate in inflammatory responses are needed to improve therapeutic approaches in liver IRI. (HEPATOLOGY 2011) Hepatic ischemia/reperfusion injury (IRI) occurs during trauma, shock, transplantation, and other surgical procedures where the blood supply to liver is temporarily interrupted. In transplantation, IRI insult can lead to a significantly higher incidence of acute and chronic rejections.