CCR6 expression in dendritic, T, and B cells suggests that this β-chemokine receptor may regulate the migration and recruitment of antigen-presenting and immunocompetent cells during inflammatory and immunological responses. Here we demonstrate that CCR6 -/-mice have underdeveloped Peyer's patches, in which the myeloid CD11b + CD11c + dendritic-cell subset is not present in the subepithelial dome. CCR6 -/-mice also have increased numbers in T-cell subpopulations within the intestinal mucosa. In 2,4-dinitrofluorobenzene-induced contact hypersensitivity (CHS) studies, CCR6 -/-mice developed more severe and more persistent inflammation than wild-type (WT) animals. Conversely, in a delayedtype hypersensitivity (DTH) model induced with allogeneic splenocytes, CCR6 -/-mice developed no inflammatory response. The altered responses seen in the CHS and DTH assays suggest the existence of a defect in the activation and/or migration of the CD4 + T-cell subsets that downregulate or elicit the inflammation response, respectively. These findings underscore the role of CCR6 in cutaneous and intestinal immunity and the utility of CCR6 -/-mice as a model to study pathologies in these tissues.
We have cloned the murine CCR6 receptor and its ligand, the L L-chemokine mMIP-3K K. Calcium mobilization assays performed with mCCR6 transfectants showed significant responses upon addition of mMIP-3K K. Murine MIP-3K K RNA is expressed in thymus, small intestine and colon, whereas mCCR6 RNA is expressed in spleen and lymph nodes. RT-PCR analysis of FACS-sorted lymphoid and antigen presenting cell subsets showed mCCR6 expression mainly in B cells, CD8^splenic dendritic cells and CD4 + T cells. The cloning and functional characterization of the mCCR6 and mMIP-3K K will allow the study of the role of these proteins in mouse models of inflammation and immunity.z 1998 Federation of European Biochemical Societies.
The hepatitis C virus (HCV) has an alternate reading frame (ARF) that overlaps the core protein gene. The overlapping reading frame distinguishes HCV from all of its known viral relatives, with the possible exception of GB virus B (GBV-B). The ARF is expressed during natural HCV infections and stimulates specific immune responses. Like several essential genes in other viruses (e.g., the human immunodeficiency virus polymerase) the ARF lacks an in-frame AUG start codon, suggesting that its expression involves unusual translation-level events. In vitro studies indicate that ribosomal frameshifting may be one of several processes that can lead to translation of the ARF. Frameshifting yields chimeric proteins that have segments encoded in the core gene covalently attached to amino acids encoded in the ARF. A consistent nomenclature for the ARF's protein products has yet to be established. We propose that all proteins that contain amino acids encoded in the + 1 ARF be called alternate reading frame proteins (ARFPs) and that specific ARFPs, such as the ARFP/F-protein, the double-frameshift protein, and the short form of core + 1, be designated as follows: ARFP/F (ARFP/F-protein), ARFP/DF (double-frameshift), and ARFP/S (short form of core + 1). The roles of ARFPs in the HCV life cycle are not yet known. There is a significant possibility that ARFPs may be responsible for some of the effects attributed to the core protein, given that most studies seeking to define the function of the core protein have employed materials likely to contain a combination of the core protein and ARFPs. The observed effects of the core protein include the induction of liver cancer, transformation of cells, and alterations of immune responses. This article reviews the discovery of ARF, describes the RNA structural elements involved in core/ARF gene expression, discusses possible functions of ARFPs, and considers the potential usefulness of ARFPs in vaccines. The HCV ARF is the focus of a new and rapidly expanding area of research, and the results of many ongoing studies are currently available in abstract form only. The preliminary nature of investigations that have not yet been reviewed by peers is noted in the text.
BACKGROUND & AIMS: Increased de novo lipogenesis creates excess intrahepatic fat and lipotoxins, propagating liver damage in nonalcoholic steatohepatitis. TVB-2640, a fatty acid synthase inhibitor, was designed to reduce excess liver fat and directly inhibit inflammatory and fibrogenic pathways. We assessed the safety and efficacy of TVB-2640 in patients with nonalcoholic steatohepatitis in the United States. METHODS: 3V2640-CLIN-005 (FASCINATE-1) was a randomized, placebo-controlled, single-blind study at 10 US sites. Adults with 8% liver fat, assessed by magnetic resonance imaging proton density fat fraction, and evidence of liver fibrosis by magnetic resonance elastography 2.5 kPa or liver biopsy were eligible. Ninetynine patients were randomized to receive placebo or 25 mg or 50 mg of TVB-2640 (orally, once-daily for 12 weeks). The primary end points of this study were safety and relative change in liver fat after treatment. RESULTS: Liver fat increased in the placebo cohort by 4.5% relative to baseline; in contrast TVB-2640 reduced liver fat by 9.6% in the 25-mg cohort (n ¼ 30; least squares mean: -15.5%; 95% confidence interval, -31.3 to -0.23; P ¼ .053), and 28.1% in the 50-mg cohort (n ¼ 28; least squares mean: -28.0%; 95% confidence interval, -44.5 to -11.6; P ¼ .001). Eleven percent of patients in the placebo group achieved a 30% relative reduction of liver fat compared to 23% in the 25-mg group, and 61% in the 50mg group (P < .001). Secondary analyses showed improvements of metabolic, pro-inflammatory and fibrotic markers. TVB-2640 was well tolerated; adverse events were mostly mild and balanced among the groups. CONCLUSIONS: TVB-2640 significantly reduced liver fat and improved biochemical, inflammatory, and fibrotic biomarkers after 12 weeks, in a dose-dependent manner in patients with nonalcoholic steatohepatitis. ClinicalTrials.gov, Number NCT03938246.
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