Serum phytosterol levels might become additional predictive biomarkers for evaluating increased risk of gallstones. A new strategy aiming at inhibiting both hepatic synthesis and intestinal absorption of cholesterol for reducing its biliary output might be envisioned for a genetically defined subgroup of individuals at a high risk for gallstones. Overall, data need to be integrated RAD001 purchase with those suggesting that the absorption of intestinal cholesterol indeed plays a role in the pathogenesis of gallstone disease, and that other groups of patients might benefit from drugs (such as ezetimibe) inhibiting

this process.11 Although the ultimate and major sources of biliary cholesterol remain to be established in different populations, a more and more intriguing story about cholesterol cholelithiasis is developing and linking with complex metabolic disturbances and genetics. This will require appropriate preventive and medicinal approaches in the future. “
“M1 activation of hepatic macrophage (MΦ）drives liver inflammation in alcoholic steatohepatitis (ASH). We have previously reported an advanced ASH produced by obesity and

alcohol in a mouse intragastric feeding (iG) model, which is characterized by heightened hepatic MΦ M1 activation with Nos2 upregulation, nitrosative stress, and hepatocyte mitochondria damage, suggesting the central role of M1 Nos2 upregulation in ASH pathogenesis. [Aim] The present study learn more tested the hypothesis that Notch pathway activates Nos2 by direct stimulation of Nos2 transcription,

metabolic reprograming, and generation of mitochondrial R〇S (mtR〇S). [Methods] M1 MΦ was isolated from the liver of iG ASH mice or produced in vitro using Raw264. 7 cells Carnitine palmitoyltransferase II treated with LPS. Expression of mitochondrial DNA (mtDNA) and nuclear genes involved in mitochondrial metabolism was evaluated by TaqMan qRT-PCR array. Notch intracellular domain (NICD) recruitment to gene promoters was assessed by ChlP; metabolic flux analysis using13C6-glucose; mitochondrial respiration by Seahorse; and mtR〇S by FACS analysis with MitoSox. [Results] Expression of Notch1, its ligand Dll4 and target Hes1, and cellular NICD1 levels are upregulated in M1 MO. NICD1 is enriched at the Nos2 promoter and the promoter activity is suppressed by Notch inhibition with y-secretase inhibitor DAPT. M1 MO has increased glucose uptake, glycolytic flux to TCA cycle, mitochondrial respiration, and mtROS, all of which are blocked or attenuated with DAPT. Pyruvate dehydrogenase (PDH) kinase, which prevents glycolyfic flux to TCA through phosphor-inhibition of PDH, is downregulated. DAPT, glycolytic inhibition with 2-deoxyglucose, and mtROS specific scavenger MitoQ attenuate the expression of Nos2 and other M1 genes.

[12, 13] In this review, we describe NGS systems and discuss the application of these advanced technologies in hepatology. THE NGS IS now generally defined as the sequencing technology that employs parallel sequencing processes producing thousands or millions of sequence reads simultaneously. Rothberg and colleagues first succeeded in sequencing the Mycoplasma genitalium genome with 96% coverage and 99.96% accuracy in a single GS20 run.[13] The GS20 was the first NGS sequencer put on the market by 454 Life Sciences. In the following years, Roche

(Basel, Switzerland) absorbed 454 Life Sciences and extended GS20 to a new version Ibrutinib of the GS FLX titanium series. The GS FLX titanium series used a parallel pyrosequencing system capable of data output from 100 Mb to 500 Mb per run with a 400–500 bp read length. The pyrosequencing of this sequencer is based on measuring the pyrophosphate generated by the DNA polymerization reaction.[14, 15] DNA is fractionated into the fragments of 300–800 bp and these DNA fragments are ligated with short adapters that contain the binding of one fragment to a MAPK Inhibitor Library cell line streptavidin-coated bead.

Emulsion polymerase chain reaction (PCR) is carried out for fragment amplification, with water droplets containing one bead and PCR reagents immersed in oil. When the PCR amplification cycles are completed, denaturation beads carrying single-stranded DNA clones are placed into the wells of a fiber-optic slide. On the slide, amplified DNA bound to each of the beads containing sulfurylase and luciferase are sequenced. When one nucleotide is added to the complementary template by the polymerase reaction, a charge-coupled device (CCD) sensor can record the light signal from luciferin. Of note, the signal strength is proportional to the number of nucleotides.[13] This technology is defined as “sequencing-by-synthesis” and is called pyrosequencing in this system. GENERALLY, THE ROCHE/GS FLX titanium series, the Solexa Genome Analyzer (Illumina, San Diego, CA, USA) and the ABI

SOLiD system are now classified as second-generation acetylcholine NGS systems. However, the GS FLX series could obtain smaller amounts of data per run than the Illumina or SOLiD systems. Therefore, some technologists believe that Illumina and SOLiD sequencers are second-generation NGS systems. The Solexa sequencing system, acquired by Illumina, was commercialized in early 2007. The Illumina Genome Analyzer is also based on the “sequencing-by-synthesis” to produce short sequence reads of millions of surface amplified DNA fragments simultaneously. Starting with fragmentation of the genome DNA, adaptor-ligated DNA fragments are attached to the surface of a glass flow cell. The flow cell is separated into eight channels and the surfaces of the channels have covalently attached oligos complementary to the adaptors and ligated to the library DNA fragments.

ACLF was the main cause of death in patients with and without RAI both during hospitalization (five versus two, respectively) and at 3 months (six versus four, respectively). Septic shock (two and one, respectively) and respiratory failure (two patients with normal adrenal function) were responsible for the remaining deaths at 3 months. Table 5 shows factors associated to the development of severe sepsis, type-1 HRS, and death at 3 months in the univariate analysis. this website Considering the low number of events observed in the study we decided to include only

four of the variables with significant predictive value in each of the multivariate models: MELD score, which reflects hepatic and renal function, both plasma renin activity and plasma noradrenaline concentration as markers of circulatory dysfunction, and delta cortisol as an estimation of adrenal function. Table 6 shows the independent predictors in the different models. Delta cortisol, a dynamic marker of adrenal function, was identified as independent risk factor of all three short-term outcomes (severe sepsis, type-1 HRS, and mortality). Our results indicate

that nearly one-fourth of noncritically ill patients with cirrhosis admitted to the hospital for the treatment of acute decompensation present RAI. Among the different methods currently available to assess 3-deazaneplanocin A datasheet adrenal function (measurements of baseline total or free cortisol levels in serum, plasma, or saliva and changes in cortisol after insulin-induced hypoglycemia or the

administration of 1 or 250 μg of adrenocorticotropic hormone [ACTH] or 1 μg/kg of corticotropin-releasing hormone)[22, 32-35] we chose the SST (increase in total serum cortisol levels 1 hour after the administration of 250 μg of ACTH, Synacthen) because it is the gold standard test used to define this entity in critical care, the setting where RAI was first described. It is also a dynamic test routinely used in the evaluation of adrenal function in clinical endocrinology.[36, 37] Among the possible criteria that can be used to define RAI using the SST: baseline serum total cortisol levels, peak serum total cortisol levels, delta cortisol, or a combination of them, we decided to use only the delta value, because as dynamic criteria it is not affected by changes Cell press in transcortin or albumin levels. Furthermore, several studies have shown that serum total cortisol overestimates the prevalence of RAI in cirrhosis due to low transcortin and albumin concentrations.[17-20] Although free cortisol levels might estimate more adequately the real prevalence of RAI in the cirrhosis population, they are not routinely used because the determination technique is complex and expensive and because diagnostic cutoff values have not been clearly defined.[22] The mechanism of RAI in cirrhosis is probably multifactorial.

[13] It improves anatomical correspondence and decreases ambiguity, which often occurs in intensity-based registration. In addition, HAMMER has been demonstrated to be only able to capitalize on the excellent anatomical resolution of a single-subject reference template, compared with the other three normalization methods used in SPM software packages, which used DARTEL, cosine basis functions and unified segmentation.[16] Given these merits, HAMMER was selected as the registration method in the following DBM analysis. The procedure was performed using HAMMER software (http://www.rad.upenn.edu/sbia/rsoftware.html). Considering that HAMMER is a

feature-based registration method, the template should be a single SC subject rather than an average atlas template because it has sharper and easily distinguishable features. Before the registration, an appropriate template image was selected by an experienced neurosurgeon. Compared with the study of Leporé and colleagues, the images of all subjects were not first aligned with the ICBM-53 brain template. Instead, they were normalized to the selected SC subject by affine transformation with 12 parameters, which reduced

their variability in orientation, position, and general size. After affine transformation, the images were warped to the template image using a multiresolution strategy. Deformation fields were generated, which described the transformation map from the template to the subject. In principle, the Jacobian matrices of the deformations are more reliable for indicating local brain shape and for reflecting the shape variations between the two groups.[17] The Jacobian matrix contains information not only on local stretching but also on shearing and rotation. The determinant of the Jacobian matrix represents the pointwise volume change induced by the transformation. That is, if the infinitesimal area

A around point in the template is mapped to an area B around point in the subject, the Oxymatrine Jacobian value quantifies the local expansion or contraction resulting from this mapping. Values above 1 indicate tissue expansion, values below 1 indicate tissue contraction, negative values indicate folding, and infinite values indicate tearing. To improve the delineation of shape CAL 101 difference patterns, the images of the Jacobian matrix were smoothened with a Gaussian filter of full-width half-maximum equal to 12 mm. The third step was statistical analysis. Given that the Jacobian value for each subject was derived with respect to the same template, all data can be compared in a voxel-by-voxel manner regardless of their shapes. A means test between the EB and SC groups was performed under the null hypothesis that the means are equal, with the assumption that the variances of the Jacobian value within the two groups are equal.

Regardless, it is easy to appreciate

how the work from these two laboratories provides hope for millions of people with certain types of liver disease. Indeed, hepatocytes from iPS cells represent a giant leap forward for hepatology. “
“See article in J. Gastroenterol. Hepatol. 2011; 26: 1145–1150. Tuberculosis (TB) remains a major challenge to human health, affecting 9.4 million and killing Y-27632 mouse 1.7 million people each year.1 Intestinal tuberculosis (ITB) is one form of extra-pulmonary TB; it most often affects the ileocecal region, but can affect any part of the gastrointestinal tract. Making a clinical diagnosis is challenging, as its non-specific symptoms of abdominal pain, fever and weight loss often mimic other diseases, particularly Crohn’s disease, adenocarcinoma and other enteric infections. Ultrasound, barium studies, computed tomography (CT) and magnetic resonance imaging (MRI) may support the diagnosis, but

imaging is often relatively non-specific. Therefore endoscopic biopsy and histological examination are usually required to confirm the diagnosis, including smear for acid-fast bacilli and culture. In high burden regions, however, empirical treatment is often instituted even without bacteriological confirmation, followed by monitoring of the patient’s response to treatment. In this edition of the Journal, Lv et al. demonstrate an association between ITB and genetic variants BMS-777607 of the intracellular proteasome, which is involved in processing protein antigens

for MHC class I-restricted presentation to CD8+ T cells.2 Their population of 168 patients all had microbiologically proven ITB; 51% of patients also had concurrent pulmonary disease, but none had disease of the selleck chemical peritoneal cavity or other viscera. This study sheds further light on the role of CD8+ T cells in response to extra-pulmonary TB. T cells play a central role in the adaptive immune response to tuberculosis infection, and the essential role of CD4+ T-cells in controlling Mycobacterium tuberculosis is well established.3 Evidence from both murine and human studies indicates that CD8+ T cells are also important for effective immunity against M. tuberculosis, through the recognition of mycobacterial peptides and lipids presented by MHC Class I and non-classical MHC molecules, respectively, on infected macrophages.4,5 These CD8+ T cells contribute to the control of infection by cytolysis of infected macrophages, augmenting cytokine production and the direct activity of secreted anti-microbial peptides.6 The key insight provided by Lv et al. is that proteosome-mediated processing of mycobacterial peptides for MHC class I presentation has an important role in the immune response to extrapulmonary TB.2 LMP2 and LMP7 (also called PSMB9 and PSMB8) are protein subunits of the multimeric proteosome, which degrades intracellular proteins into peptides.

We have previously treated these conditions with Endoscopic Mechanical Lithotripsy (EML) in our hospital, but multiple procedures were often required. Recently,

the application of Endoscopic Papillary Large Balloon Dilation (EPLBD) together with endoscopic sphincterotomy has been reported for the treatment of these conditions. We compared EPLBD cases in patients over 80 years old with those in patients under 80 years old and examined the effectiveness and safety of EPLBD for aged people. Methods: We applied EPLBD in our hospital to cases with a major axis stone of over 15 mm or more than 3 HM781-36B concentration stones. We examined 13 EPLBD cases for patients over 80 years old (Group A) and 10 cases for patients under 80 years old in the period from selleck kinase inhibitor April 2012 to February 2013. The mean ages were 86 ± 5.0 y.o. (Group A) and 74 ± 4.8 y.o. (Group B).

The mean major axes of the biliary stone were 20.3 ± 6.7 mm (Group A) and 16.7 ± 3.6 mm (Group B). The mean numbers of biliary stones were 5.0 ± 3.2 (Group A) and 4.2 ± 2.0 mm (Group B). Results: The mean procedure times were 42 ± 17 check details minutes (Group A) and 57 ± 32 minutes (Group B). The rates of procedural accidents were 1/13 (Group A) and 2/10 (Group B). The rates of the complete clearance of biliary stones in one procedure were 10/13 (Group A) and 9/10 (Group B). Conclusion: EPLBD is a safe and effective method in the treatment of aged patients. Key Word(s): 1. EPLBD Presenting Author: TOSHIHIRO NIIKURA Additional Authors: TAKAYUKI KATO, SHIGERU KOYAMA, NOBORU MISAWA, YUTARO ISHIKAWA, MINEO KANEZAKI, RYOJI SUZUKI, TETSURO FUJII, FUMITAKE JONO, KEIKO

AKIMOTO, YUMIKO HOJO, NOBUTAKA FUJISAWA, KENSUKE KUBOTA, ATSUSHI NAKAJIMA Corresponding Author: TOSHIHIRO NIIKURA Affiliations: Tokyo Metropolitan Hiroo Hospital, Tokyo Metropolitan Hiroo Hospital, Tokyo Metropolitan Hiroo Hospital, Tokyo Metropolitan Hiroo Hospital, Tokyo Metropolitan Hiroo Hospital, Tokyo Metropolitan Hiroo Hospital, Tokyo Metropolitan Hiroo Hospital, Tokyo Metropolitan Hiroo Hospital, Tokyo Metropolitan Hiroo Hospital, Tokyo Metropolitan Hiroo Hospital, Tokyo Metropolitan Hiroo Hospital, Yokohama City University, Yokohama City University Objective: Therapeutic ERCP is now the first-line therapy for common bile duct (CBD) stones.

Thus, we achieved a condition of increasing LIC in the face of stable (albeit high) circulating iron levels. In the chronic iron treatment setting, hepatic Hamp mRNA expression significantly and progressively increased between baseline and 48 hours,

and then plateaued for the remaining 3 weeks (Fig. 1D). Although both LIC and Tf sat positively correlated Sorafenib order with Hamp mRNA levels (r = 0.456, P = 0.002; r = 0.658, P < 0.001, respectively) and significantly influenced Hamp mRNA expression by simple linear regression analysis (R2 = 0.21, β = 0.456, P = 0.002; R2 = 0.43, β = 0.658, P < 0.001, respectively) by multivariate analysis, Tf sat was the only independent predictor of hepatic Hamp mRNA levels (R2 = 0.46, β = 0.57, P < 0.001) in this setting. Although the influence of LIC on Hamp mRNA levels was difficult to detect in the chronic iron treatment setting where both LIC and Tf sat were elevated, mice switched to a low iron diet buy Fulvestrant after

receiving a high iron diet for 1 week maintained a high LIC for up 8 days (Fig. 2C), whereas serum iron and Tf sat decreased back to baseline levels by 24-48 hours (Fig. 2A,B), allowing us to examine the effects of an isolated elevated LIC with normal circulating iron levels. The low iron diet significantly decreased hepatic Hamp mRNA levels from those achieved by 1 week of a high iron diet within 24 hours and for up to 8 days (Fig. 2D), reflecting the decrease in serum iron and Tf sat, and consistent with a role for circulating iron in regulating hepcidin expression. Notably, Hamp mRNA levels remained significantly elevated above baseline for up to 8 days in these mice, suggesting

an independent role for LIC in inducing hepcidin expression. Indeed, by multivariate analysis, both Tf sat and LIC were independent predictors of hepatic Hamp mRNA levels in this model (R2 = 0.856; β = 0.004, P < 0.001 for Tf sat; β = 0.0004, find more P < 0.001 for LIC). In the acute iron treatment experiment, both serum iron (Fig. 3A) and Tf sat (Fig. 3B) were significantly increased by a single dose of 2 mg/kg iron at 1 and 4 hours after oral gavage (black bars) compared with untreated animals (Baseline) or with mock gavage (gray bars), with a return to baseline by 8-24 hours. In contrast, LIC was unchanged at all timepoints in comparison to baseline and the respective mock groups (Fig. 3C). In the acute iron treatment experiment, hepatic Hamp mRNA showed a progressive temporal increase, and was significantly increased at 4 and 8 hours after iron gavage in comparison to baseline and the corresponding mock groups, with a return to baseline levels by 24 hours (Fig. 3D, black bars). The mock group did not manifest significant differences in Hamp mRNA compared to baseline, although there was a trend toward a higher value at 4 hours after mock gavage, suggesting a possible effect of the gavage procedure itself in a few animals (Fig. 3D, gray bars). In the iron group, hepatic Hamp mRNA was correlated with Tf sat (r = 0.455, P = 0.

Thus, we achieved a condition of increasing LIC in the face of stable (albeit high) circulating iron levels. In the chronic iron treatment setting, hepatic Hamp mRNA expression significantly and progressively increased between baseline and 48 hours,

and then plateaued for the remaining 3 weeks (Fig. 1D). Although both LIC and Tf sat positively correlated Roscovitine purchase with Hamp mRNA levels (r = 0.456, P = 0.002; r = 0.658, P < 0.001, respectively) and significantly influenced Hamp mRNA expression by simple linear regression analysis (R2 = 0.21, β = 0.456, P = 0.002; R2 = 0.43, β = 0.658, P < 0.001, respectively) by multivariate analysis, Tf sat was the only independent predictor of hepatic Hamp mRNA levels (R2 = 0.46, β = 0.57, P < 0.001) in this setting. Although the influence of LIC on Hamp mRNA levels was difficult to detect in the chronic iron treatment setting where both LIC and Tf sat were elevated, mice switched to a low iron diet see more after

receiving a high iron diet for 1 week maintained a high LIC for up 8 days (Fig. 2C), whereas serum iron and Tf sat decreased back to baseline levels by 24-48 hours (Fig. 2A,B), allowing us to examine the effects of an isolated elevated LIC with normal circulating iron levels. The low iron diet significantly decreased hepatic Hamp mRNA levels from those achieved by 1 week of a high iron diet within 24 hours and for up to 8 days (Fig. 2D), reflecting the decrease in serum iron and Tf sat, and consistent with a role for circulating iron in regulating hepcidin expression. Notably, Hamp mRNA levels remained significantly elevated above baseline for up to 8 days in these mice, suggesting

an independent role for LIC in inducing hepcidin expression. Indeed, by multivariate analysis, both Tf sat and LIC were independent predictors of hepatic Hamp mRNA levels in this model (R2 = 0.856; β = 0.004, P < 0.001 for Tf sat; β = 0.0004, check details P < 0.001 for LIC). In the acute iron treatment experiment, both serum iron (Fig. 3A) and Tf sat (Fig. 3B) were significantly increased by a single dose of 2 mg/kg iron at 1 and 4 hours after oral gavage (black bars) compared with untreated animals (Baseline) or with mock gavage (gray bars), with a return to baseline by 8-24 hours. In contrast, LIC was unchanged at all timepoints in comparison to baseline and the respective mock groups (Fig. 3C). In the acute iron treatment experiment, hepatic Hamp mRNA showed a progressive temporal increase, and was significantly increased at 4 and 8 hours after iron gavage in comparison to baseline and the corresponding mock groups, with a return to baseline levels by 24 hours (Fig. 3D, black bars). The mock group did not manifest significant differences in Hamp mRNA compared to baseline, although there was a trend toward a higher value at 4 hours after mock gavage, suggesting a possible effect of the gavage procedure itself in a few animals (Fig. 3D, gray bars). In the iron group, hepatic Hamp mRNA was correlated with Tf sat (r = 0.455, P = 0.

Aim: To determine whether the CLDN2 risk allele is associated with CLD or has effects unique to the pancreas. Methods Samples from patients with

CLD (ETOH, NASH, HCV, HBV, PBC, PSC) were prospectively collected and stored in our Liver Disease Biorepository. Patients with CP and healthy control patients were prospectively enrolled in the North American Pancreatitis Study 2 (NAPS2). DNA was purified from blood and genotyped using TaqMan for rs12688220. http://www.selleckchem.com/products/AZD6244.html Comparisons were made utilizing Chi Square and Fisher’s exact test. Results: 412 patients with CLD were compared with 999 patients with CP and 642 healthy control patients. The T allele frequency for all patients with CLD was similar to controls (0.23 vs 0.25, p=0.43) and was significantly less than patients with CP (0.23 vs 0.40, p<0.0001). When only patients with alcoholic liver dis ease (n=76) were analyzed, the T allele frequency was similar to controls (0.24 vs 0.25, p=0.73), and was significantly less than patients with

alcohol-induced CP (n=334) (0.24 vs 0.47, p<0.0001). No differences were seen when males and females were analyzed separately for all patients with CLD and CP. Conclusions: The AZD6738 CLDN2-loci risk allele does not strongly predispose to liver disease. The functional effects of the CLDN2-loci may be unique to the pancreas, especially with chronic alcohol consumption. Disclosures: David C. Whitcomb – Advisory Committees or Review Panels: AbbVie, Novar-tis, Millennium; Employment: UPMC, University of Pittsburgh; Grant/Research Support: NIDDK, National Pancreas Foundation, DoD; Independent Contractor: UpToDate; Patent Held/Filed: university of Pittsburgh; Stock Shareholder: SMART-MD, Ambry Genetics The

following people have nothing to disclose: Alison Jazwinski, Jyothsna Talluri, Gautam Mankaney, Jessica LaRusch, Jaideep Behari Background: Alcohol abuse leads to alcoholic liver disease (ALD) and iflammation is key to disease click here progression. Calcium-dependent signaling delivers pro-inflammatory promotes inflammation. Here we aimed to define the role of calcium-dependent signaling in liver macrophages (Mf) Kupffer cells (KC) as it relates to ALD pathogenesis. Methods: We fed alcohol (Lieber-deCarli) or control diet to control, macrophage-depleted (by exposure to clodronate liposomes) or cyclosporine-treated C57Bl6 mice. Kupffer cells (KC) and hepatocytes (Hpt) were isolated by enzymatic digestion and gradient centrifugation. Livers were analyzed by histology, RNA by PCR, protein by western blot, NFAT activity by EMSA, cytokines by ELISA and Multiplex. Results: Alcohol diet, unlike control diet, led to significant increase in serum ALT, suggestive of liver injury and serum cytokines (TNFα, IL1, IL6, KC), suggestive of inflammation, in control C57Bl6 mice.

The basal expression of H-2Kb was lower in hepatocytes compared to the other liver cells or mDC (Fig. 3C, P < 0.05). This may suggest a lower capacity of these cells to induce a T-cell response (Fig. 3). Following 4 and 24 hours of incubation with fluorescein OVA conjugate, LSECs took up more OVA compared

to other APCs (Fig. 3A; Supporting Fig. S3). Concordantly, LSECs processed more DQ OVA and displayed higher levels of H-2Kb-SIINFEKL on their cell surface (Fig. 3B,D, respectively). These results explain how LSECs show such strong cross-presentation of soluble proteins and induce T-cell proliferation. Hepatocytes and HSCs could uptake OVA protein, but less efficiently than the other liver APCs (Figs. 3; Supporting S3). Unexpectedly, we also noticed high levels of H-2Kb-SIINFEKL on the surface of HSCs after 24-hour incubation with OVA protein.

The events that lead to T-cell activation are critically regulated Ibrutinib by costimulatory molecules, such as CD28 and ICAM-1 located at the immunological synapse.20, 21 With a focus on LSECs, KCs, and spleen mDCs, we tested whether liver APCs exhibit distinctive costimulatory requirements during antigen cross-presentation and activation of CD8+ T cells. During initial experiments using blocking antibodies, we observed an important role for ICAM-1 in antigen presentation by liver cells (Fig. S2). Thus, to further address the role of ICAM-1 in cross-presentation of OVA by liver APCs, we used APCs isolated Selleckchem INCB024360 from ICAM-1-deficient mice.

ICAM-1-deficient LSECs and KCs could not cross-present soluble OVA to CD8+ T cells and failed to induce T-cell proliferation (Fig. 4, wildtype [WT] versus ICAM-1-deficient APCs, P = 0.029 for LSECs and P = 0.018 for KCs). However, ICAM-1-deficient spleen mDCs induced robust proliferation of CD8+ T cells similar to WT mDCs (Fig. 4). This suggests that ICAM-1 is particularly important in T-cell activation by liver see more APCs, in contrast to its smaller contribution to T-cell activation by spleen mDCs. The CD8+ T-cell activation response relies on the differentiation of a small number of specific naive CD8+ T lymphocytes into potent effector CTLs. One of the many facets of this activation is up-regulation of cell adhesion molecules including the hyaluronic acid receptor (CD44), and the expression of the CD25, receptor for IL-2, an important cytokine for T-cell proliferation.22, 23 We evaluated the expression of these two markers of CD8+ T-cell activation following antigen cross-presentation by liver APCs or spleen mDCs. Compared to mDCs, we observed that liver APCs induced less CD25 and CD44 expression on proliferated CD8+ cells (Fig. 5A-C). Increasing bm8-OVA hepatocyte density failed to elevate CD44 or CD25 induced by liver APCs to levels comparable to spleen mDCs (Fig. 5A,B).