Similarity levels between the salivary inocula and control microcosm Selumetinib concentration profiles were c. 70%. Plaques developed in the presence of hβD 1, hβD 2 and hβD 3 showed high levels of homology (93%) when hβDs were applied singly. Plaques grown with hβD 2 with 3 and hβD 1 with 3 in combinations were 83% and 93% similar, respectively, to their constituent hβD exposure profiles. HNP 1- and HNP 2-treated microcosms showed 86% similarity to each other. Both histatins (His 5 and His 8) dosed separately produced profiles that were 97% similar.

The effect of LL37 plaques was c. 86% similar to histatins and hβD plaques. These data in Fig. 3 indicate that (1) the eubacterial composition of the exposed micrososms diverged from those of the inocula

and (2) the presence of HDPs influenced consortial composition. The compositional effects of HDPs at physiological concentrations were assessed using an in vitro system, where oral consortia are grown in the bulk and sessile phases, representative of selleck kinase inhibitor saliva and dental plaque, respectively. This approach enabled the influence of HDPs to be differentiated from confounding factors which may be prevalent in situ, such as variations in diet and thus nutrient availability, immune factors, and variable fluid dynamic forces. The model system has been previously utilized for the maintenance and dosing of in vitro plaques (Ledder et al., 2009; Ledder & McBain, 2011).

Microscopic analysis of viability and aggregation using LIVE/DEAD staining provided an indication of plaque disposition with minimal disruption, whilst differential culture, combined with PCR-DGGE, revealed compositional effects of HDP exposure, where different peptides may exhibit specificity towards distinct taxonomic groups within the oral microbiota. HDP exposure decreased overall bacterial viability according to fluorescence microscopy with LIVE/DEAD staining (Table 2). Dimethyl sulfoxide This observation has apparently not previously been reported for physiological concentrations of HDPs in an ex situ system. Interestingly, the majority of HDPs tested decreased bacterial aggregation. Whilst this effect has been previously observed for histatins (Murakami et al., 1991), it has not to date been reported for HNPs and hβDs. Perturbation of aggregative processes can markedly influence plaque composition, where they may be involved in plaque formation through coaggregation and coadhesion (Kolenbrander & London, 1993). This could account for the fact that HDPs with apparently low antibacterial potency in pure culture assays can markedly influence plaque disposition and composition. Data generated using differential culture corroborated observations of decreased viability from microscopic analyses (Table 2). Generalized suppression of Gram-negative anaerobes by the majority of the HDPs (except His 5) was evident.

gov). Furthermore, a dose-escalating selleck kinase inhibitor phase I clinical trial was carried out in on-pump cardiac surgery patients undergoing coronary artery bypass or valve repair, who

were at high risk of developing postoperative acute kidney injury (http://www.clinicaltrials.gov; NCT00733876). Preliminary results have demonstrated that the MSC therapy resulted in no adverse effects. The postoperative length of stay and readmission rate of MSC-treated patients compared to historical matched controls was reduced by approximately 40%. All MSC-treated patients exhibited normal renal function in comparison to approximately 20% of the historical matched controls that developed acute kidney injury.53 Clinical trials investigating the use of MSC transplantation for the prevention of kidney transplant rejection and graft tolerance (http://www.clinicaltrials.gov; NCT00752479, NCT00658073 and NCT00734396), and the treatment of lupus nephritis (http://www.clinicaltrials.gov;

NCT00698191 and NCT00659217) are also currently underway. Despite the current data showing clinical efficacy, the precise manner in which MSC confer renoprotection is not understood. Initial experimental studies carried out Apitolisib by Morigi et al.54 and Herrera et al.55 reported that the exogenous administration of MSC to mice with acute renal injury could promote both structural and functional renal repair via the transdifferentiation of MSC into tubular epithelium. However, follow up studies revealed that only 2.0–2.5% of the injected MSC showed engraftment,56 for opposed to a previously reported 22% of cells.55 These reports demonstrate that the direct engraftment of exogenously administered, transdifferentiating MSC is not the predominant

mechanism in which MSC enhance renal repair. There is increasing evidence that MSC can elicit repair through paracrine and/or endocrine mechanisms, where they release trophic growth factors that modulate the immune response and consequently mediate repair.57–64 The ability of MSC to inhibit the release of pro-inflammatory cytokines and secrete a variety of trophic growth factors that, promote angiogenesis, mitogenesis and proliferation while reducing apoptosis may collectively mediate the protective and regenerative effects in the kidney of laboratory rodents (summarized in Table 1).54–70 Recent studies,60,62 have shown that the administration of MSC following ischemia-reperfusion (IR) injury result in a significant downregulation of the expression of pro-inflammatory cytokines such as IL-1β, TNF-α, IFN-γ and suppression of inducible nitric oxide synthase (iNOS) at 24 h post-IR injury. This was coupled with an upregulation of the anti-inflammatory cytokines IL-4, IL-10, basic fibroblast growth factor (bFGF), transforming growth factor (TGF)-α and Bcl-2, which resulted in a reduction in renal injury, increased tubular epithelial proliferation and improved renal function.

Ccr5[38] encodes a member of the beta chemokine receptor family, which is expressed by T cells and macrophages, and has ligands known to be important in the intestine [39]. The ptger4 gene [40] encodes a G-protein coupled receptor for prostaglandin E2 (PGE2), Acalabrutinib ic50 which activates T cell factor signalling, and ccl20 is a crucial intestinal chemotactic

factor which aids formation and function of mucosal lymphoid tissues by attracting lymphocytes and dendritic cells towards epithelial cells, and in addition possesses anti-bacterial activity [41]. The SLC22A5 gene (OCTN2) gene [42] encodes an organic cation transporter critical for elimination of endogenous organic cations, drugs and environmental toxins. The irgm product [43] regulates autophagy in response to intracellular pathogens. All these identified genes are crucial to the immune features of the intestine relevant to bacterial and toxin handling, and they share fundamental importance in our current understanding of IBD pathogenesis. By 28 days after AA (data not shown), only the tnfsf10 gene (1·6-fold) and the irgm gene (1·7-fold) remained up-regulated and the ccl20 gene (0·63-fold) was sustainedly

down-regulated, buttressing this website suggested roles for these genes in IBD pathogenesis and appendicitis-related protection against IBD. The genes chosen for RT–PCR validation were representative of immune functions pertaining to innate immunity (slpi, s100A8, lbp, CD68), cell migration (ccl8, cxcl10, ccl12, pf4, ccl5, ccl7, fpr1, ccr5) and immune-mediation (IL18R1, IL33). Additionally, these genes were represented well across many gene-sets up-regulated in the AA group (data not shown). Although the RT–PCR data at the 3-day time-point validated our microarray data, the subsequent down-regulation Amino acid of 13 of the 14 selected genes shown by RT–PCR over 28 days after surgery is indeed intriguing. This may indicate activation, repression or de-repression of these or related genes leading to downstream gene-products, culminating in the milieu responsible for the durable AA-conferred protection

against colitis. Inexplicably, CD68 was up-regulated in the SS group, although being expressed to a relatively lesser extent in the AA group. Preliminary microarray data at the 28-day post-surgery time-point indicate fundamentally different gene-sets may be implicated in the durable effect of appendicitis and appendectomy. These genes and gene-sets may indicate downstream gene expression changes owing to repression or de-repression of genes modulated at earlier (3-day) time-points (data not shown). Further analysis of these profiles and biological pathways will assist in the utilization of these gene products and manipulating various aspects of these pathways to develop better therapeutic strategies in the management of intractable IBD. National Health and Medical Research Council (NHMRC) for funding this study.

MRI revealed a large, heterogeneously enhancing intrasellar/suprasellar lesion displacing the optic chiasm and extending into the right cavernous sinus. Radiologically, these findings were thought to represent an invasive pituitary adenoma. Pterional craniotomy was performed with subtotal tumor resection. Histopathological examination revealed a T-cell lymphoblastic lymphoma/leukemia

(T-LBL) admixed with pituitary corticotrophic cell hyperplasia. CT scans of the chest, abdomen and pelvis showed no evidence of systemic disease. Analysis of peripheral blood and bone marrow, including flow cytometry, demonstrated no involvement by T-LBL. Follow-up MRI of the spine revealed abnormalities in the distal thoracic spinal cord and conus medullaris, raising suspicions of leptomeningeal dissemination. Only five case reports of T-cell primary pituitary lymphoma (PPL) have been previously described, four of which Navitoclax solubility dmso were associated with hypopituitarism and/or concurrent pituitary adenoma. We present the first report of a T-cell PPL associated with adenohypophyseal hyperplasia and the third documented occurrence of a primary pituitary T-LBL. “
“K. Donev, B. W. Scheithauer, F. J. Rodriguez click here and S. Jenkins (2010) Neuropathology and Applied Neurobiology36, 411–421

Expression of diagnostic neuronal markers and outcome in glioblastoma Background: High-grade gliomas featuring giant cells, often demonstrate immunoreactivity for neuronal markers, a finding prognostically significant according to some studies. We investigated this event in glioblastomas (GBM). Methods: Immunoexpression for synaptophysin, neurofilament protein, neuronal nuclear antigen, chromogranin and glial

fibrillary acidic protein was analysed in 82 GBM including 11 fibrillary, 8 gemistocytic, 40 giant cell and 23 small cell examples. Survival was compared between tumours exhibiting (GBMpos) or lacking (GBMneg) neuronal markers and also between tumours expressing only one vs. two or more neuronal markers. Results: Forty-five of the 82 tumours (54.8%) including 5 fibrillary, 5 gemistocytic, 30 giant cell and 5 small Epothilone B (EPO906, Patupilone) cell GBMs expressed at least one neuronal marker, synaptophysin being the most frequent (96%). There was no statistically significant difference in survival between GBMpos and GBMneg tumours, all cytologic subtypes combined (P = 0.22). The same was true when cytologic categories were compared. When only GBMpos tumours were analysed, there was a marginally significant difference in outcome between tumours positive for one vs. multiple markers (P = 0.05). This difference was influenced primarily by giant cell GBMs among which the survival time was significantly shorter in the multiple vs. single marker category (median 123 vs. 295 days, P = 0.014). This difference was not observed in the other GBM cell types. Ultrastructurally, rare neurosecretory granules in glial filament-rich cells were identified in one of four tumours studied.

Furthermore, increased distance to the closest LT center was associated with decreased odds of waitlisting, as was black race. Conclusions: There are marked geographic and racial differences in access to transplant care in the Medicaid population. These must be addressed to equitably care for the broader population of

patients with ESLD. Multivariable model evaluating waitlisting *Only variables with p<0.05 presented Disclosures: David S. Goldberg - Grant/Research Support: Bayer Healthcare James D. Lewis - Grant/Research Support: Bayer The following people have nothing to disclose: Benjamin French, Scott D. Halpern "
“The hepatitis B virus (HBV) X protein has been implicated as a potential trigger of the epigenetic modifications of some genes during hepatocarcinogenesis, but the underlying mechanisms remain unknown. MicroRNAs (miRNAs), which are noncoding Depsipeptide RNAs that regulate gene expression, are involved in diverse biological functions and in carcinogenesis. In this

study, we investigated whether some miRNAs are aberrantly expressed and involved in the regulation of the abnormal DNA methylation status in HBV-related hepatocellular carcinoma (HCC). Our results showed that the expression of microRNA-152 (miR-152) was frequently down-regulated in HBV-related HCC tissues in comparison with adjacent noncancerous hepatic tissues and was inversely correlated to DNA methyltransferase 1 (DNMT1) www.selleckchem.com/products/cobimetinib-gdc-0973-rg7420.html messenger RNA (mRNA) expression in HBV-related HCCs. The forced expression of miR-152 in liver cell lines resulted in a marked reduction of the expression of DNMT1 at both the mRNA and protein levels by directly targeting

the 3′ untranslated regions of DNMT1. This in turn led to a decrease in global DNA methylation, whereas inhibition of miR-152 caused global DNA hypermethylation and increased the methylation levels of two tumor suppressor genes, glutathione S-transferase pi 1 (GSTP1) and E-cadherin 1 (CDH1). Conclusion: Our findings suggest that miR-152 is frequently down-regulated and regulates DNMT1 in HBV-related HCC. These findings support Amrubicin a tumor-suppressive role of miR-152 in the epigenetic aberration of HBV-related HCC and the potential development of miRNA-based targeted approaches for the treatment of HBV-related HCC. HEPATOLOGY 2010 Liver cancer is the fifth most common cancer in the world and the third most common cause of cancer-related death.1 Overall, 50% to 55% of cases of primary liver cancer are attributable to persistent hepatitis B virus (HBV) infections.2 HBV causes chronic infection in approximately 400 million people in the world.3 It is estimated that 50% of male carriers and 14% of female carriers will eventually die of the complications of cirrhosis and hepatocellular carcinoma (HCC).

Since previous studies identified HIF1α regulating ENT1 and Adora2b receptor expression we used a novel mouse line with deletion of HIF1α in hepatocytes (HIF1αloxP/loxP Albumin Cre+, Fig. 7A) and studied ENT1/ENT2 and adenosine receptor expression with and without liver ischemia. Interestingly, ENT1 and ENT2 transcript levels were at baseline higher in the conditional

HIF knockout mice compared to the appropriate controls (Fig. 7B). Furthermore, neither ENT1 nor ENT2 were repressed following liver ischemia in contrast to the control mice. Moreover, the increase in Adora2b receptor transcript following liver ischemia in control mice was absent in HIF1αloxP/loxP Albumin Cre+ Akt inhibitor mice (Fig. 7C). These findings are consistent with previous studies that identified a transcriptionally regulated pathway for ENT1, ENT2, and Adora2b involving HIF.[15, 26] Together, these studies indicate that ENT1 and Adora2b are transcriptionally Buparlisib clinical trial regulated by way of HIF1α during liver ischemia and reperfusion injury. Hepatic ischemia and reperfusion injury significantly contributes to the mortality and morbidity of major hepatic surgery and liver transplantation. Moreover, therapeutic approaches to dampen ischemia and reperfusion-mediated tissue injury are extremely limited, and studies trying to identify novel therapeutic targets is an area of intense

research. Based on previous studies showing that levels of the antiinflammatory signaling molecule adenosine are tightly regulated by adenosine transporters (particularly ENTs), we pursued the hypothesis that ENTs can be targeted to increase hepatic adenosine signaling and thereby mediate liver protection from ischemia and reperfusion. Indeed, these studies demonstrated that ENT1 is particularly expressed in the human liver, and ENT1/2 transcript

levels are repressed following liver transplantation in humans. Functional studies with the ENT inhibitor dipyridamole demonstrated liver protection in conjunction with elevations of extracellular adenosine levels. Moreover, we observed a selective phenotype in Ent1−/− mice characterized by elevation of hepatic adenosine levels and profound hepatoprotection from ischemia and reperfusion injury. Subsequent studies with pharmacologic blockers of adenosine signaling revealed that the observed Lck protection in Ent1−/− mice predominantly involves Adora2b. Furthermore, we could show that Ent1/Ent2 and Adora2b are transcriptionally regulated by way of HIF1α by utilizing conditional mice. Taken together, these studies demonstrate a functional role for ENT1 in liver protection from ischemia and reperfusion injury and implicate ENT inhibitors in the treatment of ischemic liver injury. The present findings demonstrate attenuated ENT1 and ENT2 transcript levels following ischemia and reperfusion during human liver transplantation, or during murine liver ischemia and reperfusion.

PCR was performed on an iQ5 Multicolor Real-Time PCR (Bio-Rad), using the iQ5 Standard Edition Software, version 2.0. Genomic DNA (10 ng) was subjected to a two-step PCR amplification under the following conditions: 1 cycle 95°C × 3 minutes, followed by 45 cycles of 95°C × 15 seconds and 68°C × 40 seconds. Primer sequences: hAAT forward: 5′-TCCTGGGTCAACTGGGCATC-3′; hAAT reverse: 5′-CAGGGGTGCCTCCTCTGTGA-3′; Gapdh forward: 5′-CCACCCCAGCAAGGACACTG-3′; Gapdh reverse 5′-GCTCCCTAGGCCCCTCCTGT-3′. Alisertib order Dilutions of hAAT plasmid into mouse genomic DNA were used to generate copy number standards. Results were normalized to Gapdh expression. In Fah5981SB mice, a single point mutation (GA transversion) at the terminal nucleotide

of Fah exon 8 leads to mis-splicing and exon-8 deletion from the messenger RNA (mRNA). Several important criteria derived from the literature18 were considered for the design of

the gene repair vector to correct the Fah5981SB point mutation (Fig. 1A). First, the vector should not contain elements needed for driving gene expression such as promoters, enhancers, or cDNA expression cassettes. Second, the fidelity and length of homology should be maximized with the packaging capacity of AAV (4.7 kb) JQ1 cell line being the limit. Third, the position of the nucleotide targeted for repair should be at the center of the homology. A 4.5-kb PCR product homologous to murine Fah was cloned into an AAV plasmid backbone and verified by DNA sequencing. Recombinant AAV-Fah of serotypes 2 and 8 were produced and administered to Fah5981SB mice as neonates or adults. Correction of the point mutation by homologous recombination (Fig. 1B) leads to normal Fah gene and protein expression. The evaluation of homologous recombination as a strategy for gene repair has traditionally relied on detecting alterations in reporter sequences rather than correcting

a disease phenotype. Given the selective advantage of FAH+ hepatocytes in the HTI liver, Fah5981SB mice can be used to study the clinical significance of AAV-mediated gene repair by homologous recombination. Four d3 Fah5981SB neonates were intravenously injected with 1 × 1011 vg of AAV2-Fah and kept on NTBC until weaning, followed by NTBC withdrawal to select for corrected over hepatocytes. Two control groups were injected with isotonic NaCl solution. Control group I (n = 3) did not receive a course of NTBC post-weaning, continued to lose weight and died. Control group II (n = 2) did receive one course of NTBC post-weaning but failed to maintain a healthy weight and died. AAV-treated mice began to stabilize in weight at 8 weeks after treatment, suggesting the onset of sufficient liver function. At age 11 weeks, a two-thirds partial hepatectomy was performed to induce liver regeneration and subsequent episomal AAV loss. Continued clinical improvement following partial hepatectomy strongly suggested stable gene repair at the Fah locus.

The involvement of LIN28A may thus explain, at least in part, the inhibitory roles of miR-370 in HCC. Lin28 promotes tumor development in at least two independent manners.[36] First, it selectively blocks the biogenesis of a class of miRNAs, such as let-7.[34] Second, it acts as a post-transcriptional regulator by directly binding specific mRNAs.[21] The Lin28/let-7 double-negative feedback loop is one of the best-characterized examples of the modulation between an miRNA and its post-transcriptional regulator.[36] To our knowledge, let-7 is the only miRNA that has been reported to interact reciprocally with Lin28. The current study

demonstrated that LIN28A blocked GSK2118436 cost the biogenesis of miR-370 by

binding to its precursor. The mutual regulation of LIN28A and miR-370 thus represents another paradigm of the direct interaction between LIN28 and miRNA. The identification of this novel LIN28A/miRNA loop suggests that the double-negative feedback loop between tumor-suppressive miRNA and LIN28A may be a ubiquitous phenomenon in cancer pathogenesis. On the other hand, direct translational modulation of mRNAs is another crucial mechanism by which Lin28 regulates gene expression.[21] Most documented mRNA targets of LIN28A, including insulin-like growth factor-2, Oct4, cyclin A, cyclin B, cyclin-dependent kinase 4, and human epidermal growth factor receptor 2, are important CDK inhibitor for cell growth, metabolism, and cancer development.[21, 26, 40] Interestingly, we demonstrated that direct Grape seed extract binding of LIN28A to RelA/p65 mRNA promoted the translation of RelA/p65.

RelA/p65 is the key subunit of the NF-κB family, which functions as an important promoter of liver carcinogenesis.[4] Thus, post-transcriptional modulation of this crucial oncoprotein represents a novel and important mechanism whereby LIN28A may exert its tumor-promoting function, in addition to its effect on miRNAs. Most cases of HCC arise in cirrhotic livers with persistent inflammation.[1] Deeper understanding of the mechanistic link between inflammation and HCC would help to identify potential therapeutic targets for HCC. Proinflammatory transcription factors, such as NF-κB and signal transducer and activator of transcription 3, and nontranscriptional elements, such as miRNAs, often cooperate in the regulatory networks that link inflammation to cancers.[28, 41, 42] The results of our current study demonstrated that miR-370 suppressed the NF-κB pathway by inhibiting LIN28A, and the biological functions of both miR-370 and LIN28A were reversed by inactivation of the NF-κB pathway. IL-6 is a well-known target of NF-κB and plays a crucial role in inflammation, wound healing, and hepatocarcinogenesis.

Physicians taking care of patients with advanced HCC after a VB episode should individualize therapies according to clinical practice, common sense, and patient needs. Some may judge that the survival benefit in these BCLC C and D patients who received secondary prophylaxis is not clinically relevant Pifithrin-�� in vitro (average, 3 months) and that more-interventional therapies (banding ligation) should be avoided, taking into account the possible adverse effects. Nevertheless, this survival benefit is similar to the survival benefit offered with sorafenib treatment in BCLC C patients,

which also has side effects, which may affect quality of life. The present study, showing a global survival effect of prophylaxis patients with advanced HCC, provides further evidence to indicate prophylaxis in this subgroup of patients as long as their clinical condition

allows them to do so. There are several setbacks to the study. Some patients with very advanced HCC and UGI bleeding were not included in the study because no endoscopy was performed. This could lead to some bias in the results, because it is probable that these patients who were not included would be the ones who would be most likely to die. However, the decision to exclude these patients from the study was based on several TSA HDAC mw reasons. First, although suspected, the cause of the bleeding was not proven because endoscopy was not performed. It is well established that approximately one third of UGI bleeding

episodes Sirolimus supplier in patients with cirrhosis are the result of other causes, rather than esophageal varices.[40, 41] Second, most likely, the patients who would not receive endoscopy would probably be the sickest ones and therefore with the most dismal outcome. Therefore, inclusion of these patients in the analysis might further enhance the differences in the outcomes of VB in patients with and without HCC. Furthermore, and although it seems that patients with HCC without secondary prophylaxis were more sick than the ones who received secondary prophylaxis, which may have influenced the physician’s opinion, it could be that there are other factors that influenced this decision that are not included in the analysis. Unfortunately, the study design does not allow analysis of the effect of sorafenib treatment on variceal bleeding. It has been established, both in animal and human studies, that sorafenib has a portal hypotensive effect, perhaps through an inhibition of angiogenesis.[42, 43] Therefore, there could be an effect of the administration of this drug on the outcomes. In the present study, sorafenib was administered exclusively to patients with advanced HCC; therefore, it is logical to speculate that lack of sorafenib could further worsen the outcome of these patients, who already have a dismal prognosis. Another limitation of the study is the uneven distribution of the etiologies among patients with and without HCC.

4C), IFN-β protein levels remained below 4 pg/mL, and IFN-α protein was undetectable (Fig. 4D). In contrast, IL-28 and IL-29 peaked to significantly higher mRNA levels within 24-48 hours and protein levels reached up to 250 pg/mL 72 hours after HCV infection (Fig. 4C-D). Variations in ISG and IFN responses among donors did not correlate with HCV RNA levels in PHH cultures (Fig. 4E,F and Supporting Fig. 1) nor with IL28B SNPs (Supporting Fig. 2). Overall, our results demonstrate that transfection of PHH with double-stranded RNA (dsRNA) and infection with HCV reproduced the ISG and IFN expression

profile that we observed in the liver during acute HCV infection. To study the functional relevance of the strong type III IFN response during HCV infection, we examined its effect on HCV replication using Huh7-Lunet cells with a subgenomic HCV PLX3397 luciferase replicon as a readout.23 Recombinant type I (500 pg/mL) and type III IFNs (100 ng/mL) inhibited HCV replication by more than 90%, and this inhibition was almost completely abrogated by cytokine-specific neutralizing Abs (Fig. 5A). IL-29, IL-28A, and IL-28B showed 50% inhibition of HCV replication at 200-500 pg/mL (Fig. 5B), which is the maximum amount of type III IFNs that PHH produced 72 hours postinfection

(Figs. 4D and 6). Because 50% antiviral activity can also be mediated by very low concentrations of type I IFNs below the ELISA detection limit, we used an indirect method to further evaluate the relative effect of type I and III IFNs on HCV replication. Supernatants from PHH cultures harvested 72 hours post-HCV infection reduced click here HCV replication by 50% (Fig. 5C). Whereas neutralization of the supernatant with Abs against either type I (IFN-α and IFN-β) 4-Aminobutyrate aminotransferase or III IFNs (IL-28A, IL-28B, and IL-29) significantly increased HCV replication, neutralization of type III IFNs had a greater effect than neutralization of type I IFNs (P = 0.0244). This result suggests that type III IFNs contribute significantly to antiviral activity during

HCV infection. Experiments with hepatoma cell lines and TLR-stimulated macrophages suggest that type III IFNs are ISGs themselves and can be induced in a type I IFN-mediated manner.8, 24 To evaluate whether this holds true for HCV-infected PHH, we infected PHH with HCV in the presence or absence of neutralizing Abs against IFN-α and IFN-β. Whereas IL-28 secretion decreased in the presence of neutralizing Abs against type I IFNs (P = 0.0078), IL-29 production was not affected in the majority of cultures (P = not significant; Fig. 6). Thus, IL-29 can be induced independently from type I IFN signaling in HCV-infected hepatocytes. pDCs were recently shown to contribute to the induction of IFN-α and ISGs when cocultured with HCV-replicating hepatoma cells.7 We therefore asked whether this result extended to pDCs cocultured with HCV-infected PHH and to the production of type III IFNs. Less than 0.