ABSTRACT
Human herpesvirus‐6 (HHV‐6), which belongs to the betaherpesvirus subfamily, mainly replicates in T lymphocytes. Here, we show that MHC class I molecules are incorporated into HHV‐6 viral ...particles and released into the extracellular environment. In addition, HHV‐6A/B‐infected T cells showed reduced surface and intracellular expression of MHC class I molecules. The cellular machinery responsible for molecular transport appears to be modified upon HHV‐6 infection, causing MHC class I molecules to be transported to virion assembly sites.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
The aim of this study was to investigate the effect of anti-mouse IL-6 receptor monoclonal antibody (MR16-1) treatment on CD4 T cell differentiation and compared it to the effect of anti-TNF mAb ...treatment with using a murine model of experimental autoimmune uveoretinitis (EAU). C57BL/6 mice were immunized with interphotoreceptor retinoid-binding protein (IRBP) to induce ocular inflammation treatment with control IgG or MR16-1 or anti-TNF mAb. Helper T cells differentiation was analyzed during the development of EAU. Immunization with IRBP increased the frequency of Th17 cells rather than Th1 cells in the early stage of EAU. Treatment with MR16-1 on the same day as immunization (day 0) or one day after (day 1) suppressed ocular inflammation in EAU mice. Treatment with MR16-1 on day 0 inhibited the induction of Th17 cells
in vivo, and inhibited not only IRBP-responsive Th17 cells but also their Th1 counterparts and induced IRBP-responsive regulatory T (Treg) cells
in vitro. The administration of anti-TNF mAb had no significant protective effect in EAU mice. The protective effect of anti-IL-6R mAb treatment, but not anti-TNF mAb treatment on EAU correlated with the inhibition of Th17 differentiation. This finding suggests that IL-6 blockade may have a therapeutic effect on human ocular inflammation which is mediated via mechanisms distinct from those of TNF blockade. IL-6 blockade may thus represent an alternative therapy for patients with ocular inflammation who are refractory to anti-TNF mAb therapy.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Inflammatory bowel disease (IBD) is a chronic disorder of the gastrointestinal tract. Although the etiology and pathogenesis of IBD remain unknown, pro-inflammatory cytokines including IFN-γ play an ...important role in the development of IBD. Suppressor of cytokine signaling-1 (SOCS-1) is a crucial inhibitor of cytokine signaling, particularly of IFN-γ. In this study, we investigated the role of SOCS-1 in the development of murine dextran sulfate sodium (DSS)-induced colitis, a model of colitis resembling human IBD. SOCS-1 heterozygous (SOCS-1+/−) and wild-type (WT) mice were given 3% DSS dissolved in drinking water for 5 days. Activation and expression of signal transducers and activators of transcription (STAT) in colonic tissues were assessed by western blot analysis. The expression of CD4, IFN-γ, IL-4, IL-17 and Forkhead box P3 (Foxp3) in colonic lamina propria lymphocytes was analyzed by flow cytometry and cytokine concentrations in serum were measured. DSS-treated SOCS-1+/− mice developed more severe colitis than DSS-treated WT mice. Enhanced activation of STAT1, a higher ratio of CD4+IFN-γ+ T cells and a lower frequency of Foxp3+ regulatory T (Treg) cells, were observed in the colon of DSS-treated SOCS-1+/− mice compared with DSS-treated WT mice. DSS-treated SOCS-1+/− mice showed higher levels of IFN-γ in sera than did DSS-treated WT mice. Furthermore, T cell-specific SOCS-1-conditional knockout mice developed more severe colitis than control mice after DSS administration. Our findings suggest that SOCS-1, particularly in T cells, prevents the development of DSS-induced colitis in mice by inhibiting IFN-γ/STAT1 signaling and by subsequently regulating Treg cell development.
To identify molecular targets in leukemia stem cells (LSCs), this study compared the protein expression profile of freshly isolated CD34+/CD38− cells with that of CD34+/CD38+ counterparts from ...individuals with acute myelogenous leukemia (n = 2, AML) using isobaric tags for relative and absolute quantitation (iTRAQ). A total of 98 proteins were overexpressed, while six proteins were underexpressed in CD34+/CD38− AML cells compared with their CD34+/CD38+ counterparts. Proteins overexpressed in CD34+/CD38− AML cells included a number of proteins involved in DNA repair, cell cycle arrest, gland differentiation, antiapoptosis, adhesion, and drug resistance. Aberrant expression of CD82, a family of adhesion molecules, in CD34+/CD38− AML cells was noted in additional clinical samples (n = 12) by flow cytometry. Importantly, down‐regulation of CD82 in CD34+/CD38− AML cells by a short hairpin RNA (shRNA) inhibited adhesion to fibronectin via up‐regulation of matrix metalloproteinases 9 (MMP9) and colony forming ability of these cells as assessed by transwell assay, real‐time RT‐PCR, and colony forming assay, respectively. Moreover, we found that down‐regulation of CD82 in CD34+/CD38− AML cells by an shRNA significantly impaired engraftment of these cells in severely immunocompromised mice. Taken together, aberrant expression of CD82 might play a role in adhesion of LSCs to bone marrow microenvironment and survival of LSCs. CD82 could be an attractive molecular target to eradicate LSCs.
What's new?
Acute myelogenous leukemia (AML) is maintained by a subset of self‐renewing leukemia stem cells (LSCs). Thus, to effectively treat AML, treatments targeting LSCs are needed. AML cells expressing CD34 but not CD38 (CD34+/CD38‐) contain abundant LSCs and were found in this study to express a greater amount of CD82 than CD34+/CD38+ AML cells. CD82 was further found to regulate the survival of CD34+/CD38‐ AML cells and their adhesion to the bone marrow microenvironment, suggesting that this glycoprotein could be an attractive target for LSC eradication.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
The prognosis of patients with advanced gastric cancer (GC) remains poor despite the recent advances in molecular targeted therapies, and the search for biomarkers that can predict prognosis and ...additional new agents with acceptable toxicity profiles are needed. Lipolysis-stimulated lipoprotein receptor (LSR) is a lipoprotein receptor that binds to triglyceride-rich lipoproteins and related to some malignancies. Herein, we examined the association between LSR expression and the prognosis of patients with GC, and investigated the antitumor effect of a previously developed anti-human LSR monoclonal antibody (#1-25). We first performed immunohistochemical analysis of LSR protein expression in GC and normal tissues, and then examined its association with the prognosis of 110 patients with GC. LSR was overexpressed in most of primary GC and metastatic tumors, but not in normal tissues. Patients with strong LSR expression (
= 80, 72.7%) had significantly poorer overall survival (OS) than those with weak expression (
= 0.017). Multivariate analysis identified strong LSR (as well as pT) as independent and significant prognostic factors for OS. Next, we demonstrated that very low density lipoprotein (VLDL) treatment increases cell proliferation in LSR-expressing GC cell lines
; LSR inhibition using #1-25 inhibited VLDL-induced proliferation by suppressing JAK/STAT and PI3K signaling.
, we demonstrated a marked antitumor effect of #1-25 in 2 distinct GC cell line xenograft mice models. Our findings suggest that LSR plays a key functional role in GC development, and that this antigen can be therapeutically targeted to improve GC treatment.
Despite the revolutionary effects of imatinib on advanced gastrointestinal stromal tumors (GISTs), most patients eventually develop disease progression following primary resistance or acquired ...resistance driven by secondary‐resistant mutations. Even in radiographically vanishing lesions, pathology has revealed persistent viable cells during imatinib therapy, which could lead to the emergence of drug‐resistant clones. To uncover the mechanisms underlying these clinical issues, here we examined imatinib‐induced phosphoproteomic alterations in GIST‐T1 cells, using our quantitative tyrosine phosphoproteomic analysis method, which combined immunoaffinity enrichment of phosphotyrosine‐containing peptides with isobaric tags for relative and absolute quantitation (iTRAQ) technology. Using this approach, we identified 171 tyrosine phosphorylation sites spanning 134 proteins, with 11 proteins exhibiting greater than 1.5‐fold increases in tyrosine phosphorylation. Among them, we evaluated FYN and focal adhesion kinase (FAK), both of which are reportedly involved in proliferation and malignant alteration of tumors. We confirmed increased tyrosine phosphorylation of both kinases by western blotting. Inhibition of FYN and FAK phosphorylation each increased tumor cell sensitivity to imatinib. Furthermore, a FAK‐selective inhibitor (TAG372) induced apoptosis of imatinib‐resistant GIST‐T1 cells and decreased the imatinib IC50. These results indicate that FYN or FAK might be potential therapeutic targets to overcome resistance to imatinib in GISTs. Additionally, we showed that the iTRAQ‐based quantitative phosphotyrosine‐focused phosphoproteomic approach is a powerful method for screening phosphoproteins associated with drug resistance.
What's new?
While the targeted tyrosine kinase inhibitor imatinib can significantly improve two‐year survival rates for patients with gastrointestinal stromal tumor (GIST), primary and secondary resistance mutations often limit its benefits. This study of the human GIST‐T1 cell line suggests that imatinib‐induced increases in tyrosine phosphorylation of FYN kinase and focal adhesion kinase (FAK) may be responsible for mediating some instances of imatinib resistance and therefore may be potential targets for killing persistent tumor cells and overcoming resistance. The findings also indicate that iTRAQ‐based quantitative phosphotyrosine‐focused proteomic analysis is a useful way of screening for phosphoproteins associated with drug resistance.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Summary
Given no reliable therapy for advanced malignant melanoma, it is important to elucidate the molecular mechanisms underlying the disease progression. Using a quantitative proteomics approach, ...the ‘isobaric tags for relative and absolute quantitation (iTRAQ)’ method, we identified that the extracellular matrix protein, periostin (POSTN), was highly expressed in invasive melanoma compared with normal skin. An immunohistochemical analysis showed that POSTN was expressed in all invasive melanoma (n = 20) and metastatic lymph node (n = 5) tissue samples, notably restricted in their stroma. In terms of the intercellular regulation of POSTN, we found that there was upregulation of POSTN when melanoma cells and normal human dermal fibroblasts (NHDFs) were cocultured, with restricted expression of TGF‐β1 and TGF‐β3. In a functional analyses, recombinant and NHDF‐derived POSTN significantly accelerated melanoma cell proliferation via the integrin/mitogen‐activated protein kinase (MAPK) signaling pathway in vitro. The size of implanted melanoma tumors was significantly suppressed in POSTN/Rag2 double knockout mice compared with Rag2 knock‐out mice. These results indicate that NHDF‐derived POSTN accelerates melanoma progression and might be a promising therapeutic target for malignant melanoma.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
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