Fanlei Hu

Peking University People's Hospital, Peping, Beijing, China

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Publications (21)67.27 Total impact

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    ABSTRACT: Recently, our research group identified the non-deleted (functional) leucocyte immunoglobulin-like receptor A3 (LILRA3) as a new genetic risk for rheumatoid arthritis.
    Annals of the rheumatic diseases. 06/2014;
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    ABSTRACT: The high temperature requirement A1 (HTRA1) is a potent protease involved in many diseases, including rheumatoid arthritis (RA). However, the regulatory mechanisms that control HTRA1 expression need to be determined. In this study, we demonstrated that IFN-γ significantly inhibited the basal and LPS-induced HTRA1 expression in fibroblasts and macrophages, which are two major cells for HTRA1 production in RA. Importantly, the inhibitory effect of IFN-γ on HTRA1 expression was evidenced in collagen-induced arthritis (CIA) mouse models and in human RA synovial cells. In parallel with the enhanced CIA incidence and pathological changes in IFN-γ-deficient mice, HTRA1 expression in the joint tissues was also increased as determined by real-time PCR and Western blots. IFN-γ deficiency increased the incidence of CIA and the pathological severity in mice. Neutralization of HTRA1 by Ab significantly reversed the enhanced CIA frequency and severity in IFN-γ-deficient mice. Mechanistically, IFN-γ negatively controls HTRA1 expression through activation of p38 MAPK/STAT1 pathway. Dual luciferase reporter assay and chromatin immunoprecipitation analysis showed that STAT1 could directly bind to HTRA1 promoter after IFN-γ stimulation. This study offers new insights into the molecular regulation of HTRA1 expression and its role in RA pathogenesis, which may have significant impact on clinical therapy for RA and possibly other HTRA1-related diseases, including osteoarthritis, age-related macular degeneration, and cancer.
    Journal of immunology (Baltimore, Md. : 1950). 06/2014;
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    ABSTRACT: As an important feature of rheumatoid arthritis (RA), an excessive amount of pro-inflammatory cytokines in RA synovial lesions induces the proliferation of synovial fibroblasts, cartilage erosion and systemic inflammatory immune response. Wnt inhibitor, Dkk-1, contributes to joint remodeling. This study was conducted to explore the role of Dkk-1 in the regulation of pro-inflammatory cytokine secretion.
    Zhonghua yi xue za zhi. 06/2014; 94(23):1777-80.
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    ABSTRACT: Interleukin (IL)-33 is a proinflammatory cytokine contributing to the pathogenesis of rheumatoid arthritis (RA). The gene encoding IL-33 may serve as a genetic factor and be associated with the risk of RA. To investigate the potential association between IL33 and RA, we performed a case-control study based on Chinese Han population. A three-stage case-control study was performed. Two tag single-nucleotide polymorphisms (SNPs) (rs7044343 and rs10975514) mapping to the IL33 gene were first genotyped in the discovery population. We further genotyped rs7044343 and rs10975514 in the validation and replication population. The associations between the two tag SNPs and phenotypic subgroups of RA and levels of serum IL-33 were assessed by logistic regression model. In the discovery population, the CC genotype of rs7044343 was associated with RA patients (Odds ratio (OR) = 0.777, 95% confidence intervals (CI) 0.611 to 0.988, P = 0.040). After anti-citrullinated peptide antibody (ACPA) stratification, the CC genotype of rs7044343 was also showed to be a protective genotype in RA without ACPA (OR = 0.610, 95% CI 0.379 to 0.982, P = 0.042). In the validation population and replication population, the association between rs7044343 and RA, especially ACPA-negative RA was still significant. A meta-analysis of discovery, validation and replication panels conferred the association between CC genotype of rs7044343 and RA (Pcombined = 0.0004; ORcombined = 0.77, 95% CI 0.67 to 0.89). There was no evidence for heterogeneity between three sample sets (Phet = 0.99, I2 = 0%). Similar results were also obtained in ACPA-negative RA (Pcombined = 0.0002; ORcombined = 0.57, 95% CI 0.43 to 0.77). No association was detected between rs10975514 polymorphism and RA susceptibility in the discovery and validation population. The serum levels of IL-33 were significantly lower in the patients with rs7044343 CC genotype. The CC genotype of rs7044343 in IL33 is associated with RA patients and downregulates IL-33 expression in RA.
    Arthritis research & therapy 04/2014; 16(2):R105. · 4.27 Impact Factor
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    ABSTRACT: Leukocyte immunoglobulin-like receptor A3 belongs to a family of receptors with inhibitory or activating functions. Since Caucasian individuals lacking LILRA3 have been found to be susceptible to multiple sclerosis and Sjögren's syndrome, we undertook this study to examine whether LILRA3 deletion is a novel genetic risk factor for rheumatoid arthritis (RA) (another autoimmune disease), whether there are sex-specific effects, and whether LILRA3 influences the subtype and severity of RA. The LILRA3 deletion and its tagging single-nucleotide polymorphism rs103294 were genotyped in a Northern Han Chinese cohort (N-Han) (1,618 cases and 1,658 controls) and a Southern Han Chinese cohort (S-Han) (575 cases and 549 controls). Association analyses were performed on the complete data set and subsets. The effect of the nondeleted (functional) LILRA3 allele on radiographic severity and LILRA3 expression was evaluated. In the N-Han discovery cohort, we unexpectedly observed a higher frequency of the functional LILRA3 in RA patients compared with healthy individuals (10.1% versus 6.3%; P = 4.01 × 10(-5) , odds ratio [OR] 1.92). The association was replicated in the S-Han cohort and confirmed by meta-analysis (P = 5.63 × 10(-6) , OR 1.83). Functional LILRA3 conferred greater risk for RA in males (P = 1.09 × 10(-6) , OR 4.47), and was specifically associated with anti-citrullinated protein antibody (ACPA)-positive RA (P = 3.05 × 10(-4) , OR 1.75). Furthermore, functional LILRA3 was associated with higher radiographic scores in ACPA-positive patients with early RA (P = 9.70 × 10(-3) ) and higher LILRA3 messenger RNA levels (P = 3.31 × 10(-8) ). Our study provides the first evidence that functional LILRA3 is a novel genetic risk factor for RA, especially in males. It appears to highly predispose to ACPA-positive RA and confers an increased risk of disease severity in patients with early RA.
    Arthritis & rheumatology (Hoboken, N.J.). 04/2014; 66(4):822-30.
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    ABSTRACT: Objective. To investigate the expression and clinical significance of trans-membrane MerTK (mMer) on circulating CD14+ monocytes/macrophages and soluble MerTK (sMer) levels in plasma in systemic lupus erythematosus (SLE). Method. 108 SLE patients and 42 healthy controls were recruited in this study. The expression of mMer on the surfaces of CD14+ monocytes/macrophages was evaluated by flow cytometry (FCM). The sMer levels were measured by ELISA. Real-time quantitative PCR was applied to evaluate the mRNA levels of MerTK and ADAM17. Results. Both mMer expression on CD14+ monocytes/macrophages and sMer levels in plasma significantly increased in SLE patients compared to healthy subjects. The frequency of anti-inflammatory MerTK expressing CD14+CD16+ monocytes decreased in SLE. mMer expression was positively correlated with CD163 expression on CD14+ cells. Both the mMer expression on CD14+ monocytes/macrophages and sMer levels in plasma were positively correlated with SLEDAI. Furthermore, more elevated mMer and sMer levels were found in patients with higher SLEDAI, presence of anti-SSA, anti-Sm autoantibodies, and lupus nephritis. Conclusion. Both mMer and sMer levels significantly increased in SLE and positively correlated with disease activity and severity. The upregulation of MerTK expression may serve as a biomarker of the disease activity and severity of SLE.
    Journal of immunology research. 01/2014; 2014:431896.
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    ABSTRACT: Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by synovial fibroblast hyperplasia and bone and cartilage erosion. Synovial fibroblast- and T cell-mediated inflammation plays crucial roles in the pathogenesis of RA. However how this inflammation is initiated, propagated, and maintained remains controversial. Here, we systemically examined the contribution of toll-like receptors (TLRs) to the inflammatory mediator production as well as Th1 and Th17 cell hyperactivity in RA. Our results show that rheumatoid arthritis synovial fibroblasts (RASF) express a series of TLRs, including TLR2, TLR3, TLR4, and TLR9, with the predominant expression of TLR3. Moreover, the expression levels of these TLRs were higher than those in osteoarthritis synovial fibroblasts (OASF). Ligation of TLR3, as well as TLR2 and TLR4, resulted in vigorous production of inflammatory cytokines, matrix metalloproteinases (MMPs), and vascular endothelial growth factor (VEGF) in RASF, with activation of the NF-κB, MAPK, and IRF3 pathways. More important, activation of these TLRs expressed by RASF exacerbated inflammatory Th1 and Th17 cell expansion both in cell-cell contact-dependent and inflammatory cytokine-dependent manners, which induced more IFN-γ and IL-17 accumulation. Targeting TLRs may modulate the inflammation in RA and provide new therapeutic strategies for overcoming this persistent disease.
    PLoS ONE 01/2014; 9(6):e100266. · 3.53 Impact Factor
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    ABSTRACT: The protease high temperature requirement A1 (HTRA1) is closely associated with rheumatoid arthritis (RA). The molecular mechanisms that control HTRA1 expression are currently unknown. We herein determined the regulatory role of toll-like receptors (TLRs) on HTRA1 expression in the collagen-induced arthritis (CIA) mouse model and synovial cells of RA patients. HTRA1 mRNA and protein production of mouse fibroblasts and macrophages, and freshly isolated RA-patient synovial cells treated with TLR ligands were detected by real-time PCR and ELISA. The incidence and arthritis severity were determined using clinical scores and histopathologic analysis. Involvement of HTRA1 in LPS-increased arthritis incidence and severity in mice was determined using anti-HTRA1 mAb. The signal pathways involved in HTRA1 expression were accessed by specific inhibitors, RNAi, dual luciferase reporter and ChIP methods RESULTS: LPS and tenascin-C but not other tested TLR ligands strongly induced HTRA1 expression. LPS significantly increased HTRA1 expression in the joint tissues as well as arthritis incidence and severity in CIA mice. Blocking HTRA1 by antibody significantly decreased LPS-promoted CIA severity. Inhibiting NF-κB significantly decreased LPS-induced HTRA1 expression in mouse and human cells. Dual luciferase reporter assay and ChIP analysis showed that p65 directly binds to HTRA1 promoter (AA-347). TLR4 activation increases HTRA1 expression through the NF-κB pathway in fibroblasts and macrophages. HTRA1 expression is involved in the enhancing effects of LPS on CIA. This study offers new insights into the regulation of HTRA1 expression via LPS/TLR4 and the role of HTRA1 in (rheumatoid) arthritis pathogenesis. © 2013 American College of Rheumatology.
    Arthritis & Rheumatology 08/2013; · 7.48 Impact Factor
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    ABSTRACT: OBJECTIVES: Hyperplasia of synovial fibroblasts, infiltration with lymphocytes and tissue hypoxia are major characteristics of rheumatoid arthritis (RA). Extensive data support a key role for toll-like receptors (TLRs) in RA. Little is known regarding the impact of hypoxia on TLR-induced inflammation in RA. The aim of this study was to reveal the effects of hypoxia and its regulator, hypoxia-inducible factor-1α (HIF-1α), on the inflammatory response of RA synovial fibroblasts (RASF) to TLR ligands. METHODS: Hypoxia was induced in RASF by incubation with Na2S2O4. TLR3 ligand polyIC, TLR2 ligand peptidoglycan, TLR4 ligand LPS and TLR9 ligand CpG were used to stimulate the cells. Effects of hypoxia on TLR-induced inflammatory mediators were determined by RT-PCR, qPCR and ELISA. Overexpression of HIF-1α as well as knocking-down its expression was used to reveal its fundamental role. RASF-induced inflammatory T cell expansion was determined by flow cytometry analysis of T helper (Th)1/Th17 cells, and IFN-γ/IL-17 production by ELISA after RASF/T cell coculture. RESULTS: Hypoxia potentiated the expression of inflammatory cytokines, metalloproteinases and VEGF in RASF stimulated by different TLR ligands, especially polyIC, a synthetic mimic of dsRNA from viruses or apoptotic cells. HIF-1α played a fundamental role in this synergy. Moreover, HIF-1α overexpression enhanced RASF-mediated expansion of inflammatory Th1 and Th17 cells, leading to proinflammatory IFN-γ and IL-17 production. CONCLUSIONS: Our findings suggest that hypoxia and HIF-1α may function in conjunction with TLR-stimulated innate immune responses to drive inflammation in RA. This pathway may serve as a therapeutic target for the disease.
    Annals of the rheumatic diseases 05/2013; · 8.11 Impact Factor
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    ABSTRACT: The purpose of this study is to investigate the therapeutic effects of a novel histone deacetylase inhibitor (HDACi), NK-HDAC-1, on collagen-induced arthritis (CIA) and pathogenic fibroblast-like synoviocytes (FLSs) from patients with rheumatoid arthritis (RA). The proliferation and apoptosis of FLSs treated with NK-HDAC-1 were evaluated by flow cytometry and fluorescence staining. The effect of NK-HDAC-1 treatment on pro-inflammatory cytokine production was determined by ELISA. CIA was established in DBA/1 mice, and NK-HDAC-1 or vehicle was administered daily after the onset of arthritis. Clinical and histological scores were calculated to assess the therapeutic efficacy of NK-HDAC-1. NK-HDAC-1 significantly inhibited the proliferation of FLSs through cell cycle arrest at the G2/M checkpoint and enhanced apoptosis of FLSs. The activity of caspases was increased during NK-HDAC-1 treatment. IL-6 production by FLSs was also suppressed by NK-HDAC-1. Furthermore, the oral administration of NK-HDAC-1 significantly enhanced synoviocyte apoptosis in vivo and inhibited CIA progression. Compared with subcroylanilide hydroxamic acid which exhibited moderate prophylactic efficacy, NK-HDAC-1 demonstrated therapeutic efficacy in CIA. NK-HDAC-1 is a novel HDACi that may ameliorate inflammatory arthritis by regulating the activation, apoptosis, and inflammatory responses of FLSs. This is the first study to support that NK-HDAC-1 may be a potential therapeutic agent for RA.
    Inflammation 04/2013; · 2.46 Impact Factor
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    ABSTRACT: Hyperplasia of synovial fibroblasts, infiltration with inflammatory cytokines, and tissue hypoxia are the major characteristics of rheumatoid arthritis (RA). Interleukin 33 (IL-33) is a newly identified inflammatory cytokine exacerbating the disease severity of RA. Hypoxia-inducible factor-1α (HIF-1α) showed increased expression in RA synovium and could regulate a number of inflammatory cytokine productions. Nevertheless, its correlation with IL-33 remains largely unknown. Here, we showed that elevated levels of IL-33 were demonstrated in RA patient synovial fluids, with upregulated expression of HIF-1α and IL-33 in the synovial fibroblasts. Knocking down HIF-1α compromised IL-33 expression in rheumatoid arthritis synovial fibroblasts (RASF), while enforcing HIF-1α expression in RASF substantially upregulated IL-33 levels. HIF-1α promoted the activation of the signalling pathways controlling IL-33 production, particularly the p38 and ERK pathways. Moreover, we showed for the first time that IL-33 in turn could induce more HIF-1α expression in RASF, thus forming a HIF-1α/IL-33 regulatory circuit that would perpetuate the inflammatory process in RA. Targeting this pathological pathway and HIF-1α may provide new therapeutic strategies for overcoming the persistent and chronic inflammatory disease.
    PLoS ONE 01/2013; 8(8):e72650. · 3.53 Impact Factor
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    ABSTRACT: Objectives. IL-33, a newly found cytokine which is involved in joint inflammation, could be blocked by a decoy receptor-sST2. The expression and correlation of IL-33 and sST2 in rheumatoid arthritis (RA) are of great interest. Methods. Synovial fluid (SF) was obtained from 120 RA and 30 osteoarthritis (OA) patients, and paired sera were collected from 54 of these RA patients. The levels of IL-33 and sST2 were measured by ELISA. Results. SF IL-33 was significantly higher in RA than in OA, which was correlated with disease activity score 28, erythrocyte sedimentation rate, rheumatoid factor (RF)-IgM, RF-IgG, glucose phosphate isomerase (GPI), and immunoglobulin. Serum IL-33 was correlated positively with SF IL-33 in RA. Furthermore, it was correlated with RF-IgM and GPI. sST2 was partly detectable in RA (13 out of 54, 24.1%), while not in OA. Serum sST2 in RA had no significant correlation with serum IL-33 or SF IL-33. However, SFs from both RA and OA patients did not express sST2. Conclusions. This study supported that IL-33 played an important role in the local pathogenesis of RA. Considering the tight correlation between IL-33 and clinical features, it may become a new target of local treatment.
    Clinical and Developmental Immunology 01/2013; 2013:985301. · 3.06 Impact Factor
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    ABSTRACT: Expression of immunoglobulin (Ig), a marker characteristic of B-cells, has been reported in epithelial cells and has been suggested to play a role in their survival and growth. We assessed the frequency and level of Ig gamma heavy chain (IgG) expression in acute myeloid leukemia (AML), and found that IgG was expressed at a high frequency and level in AML cell lines and primary myeloblasts, but not in monocytes or neutrophils from patients with non-hematopoietic neoplasms or healthy controls. AML-derived IgG had the same molecular weight as B-cell-derived IgG and was secreted. We further detected IgG V(H)DJ(H) transcripts in AML cell lines and sorted primary myeloblasts, confirming that IgG expression was indeed produced by AML cells. AML-derived IgG gene rearrangements showed evidence of somatic hypermutation of the variable (V) gene segments, and restricted (AML cell lines) or biased (primary myeloblasts) V usage. Anti-human IgG reduced cell viability and induced apoptosis in AML cell lines. Although the function of the AML-derived IgG is unclear, our findings suggest that AML-derived IgG may be a novel AML-related gene that contributes to leukemogenesis and AML progression. AML-derived IgG may serve as a useful molecular marker for monitoring minimal residual disease or designing target therapy.Leukemia accepted article preview online, 9 July 2012; doi:10.1038/leu.2012.184.
    Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 07/2012; · 10.16 Impact Factor
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    ABSTRACT: Human transcriptional adaptor hADA2a is an important component of the general control nonderepressible 5 (GCN5) histone acetyltransferase complex. Here, we report that coiled-coil domain containing 134 (CCDC134), a novel nuclear protein, binds to hADA2a and enhances the stability of the hADA2a protein in unstressed conditions. Furthermore, CCDC134 was found to participate in the p300/CBP-associated factor (PCAF) complex via hADA2a and affect the histone acetyltransferase activity of the complex. We also found that CCDC134 increased the PCAF-dependent K320 acetylation of p53 and p53 protein stability in the presence of hADA2a overexpression. Moreover, we demonstrated the biological significance of the interaction between CCDC134 and hADA2a. CCDC134 showed obvious nuclear accumulation after ultraviolet (UV) irradiation, and the knockdown of endogenous CCDC134 suppressed hADA2a-induced cell apoptosis activity and G1/S cell cycle arrest. Together, our findings indicate that CCDC134 might act as a novel regulator of hADA2a, and plays roles in the PCAF complex via hADA2a to affect its acetyltransferase activity and UV-induced DNA damage repair.
    Histochemie 05/2012; 138(1):41-55. · 2.61 Impact Factor
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    ABSTRACT: It is well known that B-1 B cells are the main cell type that is responsible for the production of natural immunoglobulin M (IgM) and can respond to infection by increasing IgM secretion. However, we unexpectedly found that some epithelial cells also can express rearranged IgM transcript that has natural IgM characteristics, such as germline-encoded and restricted rearrangement patterns. Here we studied IgM expression in human non-B cells and found that IgM was frequently expressed by many human epithelial cancer cells as well as non-cancer epithelial cells. Moreover, CD79A and CD79B, two molecules that are physically linked to membranous IgM on the surface of B cells to form the B cell antigen receptor complex, were also expressed on the cell surface of epithelial cancer cells and co-located with IgM. Like the natural IgM, the epithelial cancer cell-derived IgM recognized a series of microbial antigens, such as single-stranded DNA, double-stranded DNA, lipopolysaccharide, and the HEp-2 cell antigen. More important, stimulation of the toll-like receptor 9 (TLR9), which mimics bacterial infection, substantially increased the secretion of IgM in human epithelial cancer cells. These findings indicate that human epithelial cancer cells as well as non-cancer epithelial cells can spontaneously produce IgM with natural antibody activity.
    PLoS ONE 01/2012; 7(12):e51423. · 3.53 Impact Factor
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    ABSTRACT: Pattern recognition scavenger receptor SRA/CD204, primarily expressed on specialized antigen-presenting cells (APCs), including dendritic cells (DCs) and macrophages, has been implicated in multiple physiological and pathological processes, including atherosclerosis, Alzheimer's disease, endotoxic shock, host defense, and cancer development. SRA/CD204 was also recently shown to function as an attenuator of vaccine response and antitumor immunity. Here, we, for the first time, report that SRA/CD204 knockout (SRA(-/-)) mice developed a more robust CD4(+) T cell response than wild-type mice after ovalbumin immunization. Splenic DCs from the immunized SRA(-/-) mice were much more efficient than those from WT mice in stimulating naïve OT-II cells, indicating that the suppressive activity of SRA/CD204 is mediated by DCs. Strikingly, antigen-exposed SRA(-/-) DCs with or without lipopolysaccharide treatment exhibited increased T-cell-stimulating activity in vitro, which was independent of the classical endocytic property of the SRA/CD204. Additionally, absence of SRA/CD204 resulted in significantly elevated IL12p35 expression in DCs upon CD40 ligation plus interferon gamma (IFN-γ) stimulation. Molecular studies reveal that SRA/CD204 inhibited the activation of STAT1, mitogen activated protein kinase p38, and nuclear factor-kappa B signaling activation in DCs treated with anti-CD40 antibodies and IFN-γ. Furthermore, splenocytes from the generated SRA(-/-) OT-II mice showed heightened proliferation upon stimulation with OVA protein or MHC-II-restricted OVA(323-339) peptide compared with cells from the SRA(+/+) OT-II mice. These results not only establish a new role of SRA/CD204 in limiting the intrinsic immunogenicity of APCs and CD4(+) T cell activation but also provide additional insights into the molecular mechanisms involved in the immune suppression by this molecule.
    Journal of Molecular Medicine 11/2011; 90(4):413-26. · 4.77 Impact Factor
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    ABSTRACT: Given the primary expression of scavenger receptor A (SRA) or CD204 on antigen-presenting cells, we investigate the immunoregulatory activities of SRA/CD204 in the context of cross-presentation of cell-associated antigen and the immunogenicity of dying tumor cells. Immunization with dying prostate cancer cells results in profoundly increased control of subsequently inoculated tumors in SRA/CD204 knockout mice. Using OVA-expressing RM1 prostate tumor line (RM1-OVA), we show for the first time that SRA absence greatly enhances dendritic cells (DCs)-mediated cross-presentation of OVA antigen derived from dying RM1 cells. While the phagocytic ability of DCs is not significantly impacted by the lack of SRA/CD204, DCs deficient in SRA/CD204 display increased expression of inflammatory cytokines and chemokines, as well as co-stimulatory molecules upon interaction with dying RM1 cells, implicating a suppressive regulation of the functional activation of DCs by SRA/CD204. Further, SRA/CD204-deficient DCs pulsed with dying RM1-OVA cells are more effective than wild-type counterparts in priming antigen-specific T-cell responses, resulting in improved control of RM1 tumor growth in both prophylactic and therapeutic settings. Our findings suggest that the increased immunogenicity of dying tumor cells in SRA/CD204 knockout mice is attributed to the altered functions of DCs in the absence of SRA/CD204, which underscores the important role of SRA/CD204 in host immune homeostasis. Selective downregulation or blockade of this immunoregulatory molecule may lead to enhanced potency of DC-based vaccines capable of breaking immune tolerance against cancer.
    Immunology and Cell Biology 03/2011; 90(1):101-8. · 3.93 Impact Factor
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    ABSTRACT: Multiple physiological and pathological conditions interfere with the function of the endoplasmic reticulum (ER). However, much remains unknown regarding the impact of ER stress on inflammatory responses in dendritic cells (DCs) upon the recognition of pathogen molecules. We show that ER stress greatly potentiates the expression of inflammatory cytokines and IFN-β in murine DCs stimulated by polyIC, a synthetic mimic of virus dsRNA. Both toll-like receptor 3 and melanoma differentiation-associated gene-5 are involved in the enhanced IFN-β production, which is associated with increased activation of NF-κB and IRF3 signaling as well as the splicing of X-box-binding protein-1 (XBP-1), an important regulator involved in ER stress response. Surprisingly, silencing of XBP-1 reduces polyIC-stimulated IFN-β expression in the presence or absence of ER stress, indicating that XBP-1 may be essential for polyIC signaling and ER stress-amplified IFN-β production. Overexpression of a spliced form of XBP-1 (XBP-1s) synergistically augments polyIC-induced inflammatory response. For the first time, we show that XBP-1s overexpression-enhanced IFN-β production in DCs markedly suppresses vesicular stomatitis virus infection, revealing a previously unrecognized role for XBP-1 in an antiviral response. Our findings suggest that evolutionarily conserved ER stress response and XBP-1 may function collaboratively with innate immunity to maintain cellular homeostasis.
    European Journal of Immunology 02/2011; 41(4):1086-97. · 4.97 Impact Factor
  • Cell Biology International - CELL BIOL INT. 01/2010; 34(8).
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    ABSTRACT: DCUN1D3 (DCN1, defective in cullin neddylation 1, domain containing 3) was found during the process of high throughput screening of novel human genes associated with serum response element (SRE) pathway activation. The DCUN1D3 gene is highly conserved among vertebrates. Human DCUN1D3 complementary DNA (cDNA) encodes 304 amino acids with an apparent molecular mass of 34 kDa. However, there has been no report about the function of DCUN1D3. This study detected that DCUN1D3 was broadly expressed in several tumor tissues and cultured cell lines; however, UVC irradiation of different doses significantly increased DCUN1D3 expression level in these cancer cell lines. Over-expression of the DCUN1D3 inhibits cell growth in HeLa. When the DCUN1D3 gene was silenced by siRNA in UVC-treated HeLa, the cell cycle in S phase was remarkably blocked; furthermore, the UVC-induced cell death was inhibited. In addition, DCUN1D3 localized mainly in the cytoplasm and perinuclear, but after UVC treatment, the DCUN1D3 gradually entered the nucleus. All the results above indicate that DCUN1D3 is a novel UVC-response gene involved in cell cycle regulation and cell survival.
    Cancer Science 10/2008; 99(11):2128-35. · 3.48 Impact Factor

Publication Stats

51 Citations
67.27 Total Impact Points

Institutions

  • 2012–2014
    • Peking University People's Hospital
      Peping, Beijing, China
  • 2011–2012
    • Peking University
      • • School of Basic Medical Science
      • • Center for Human Disease Genomics
      Peping, Beijing, China
    • Virginia Commonwealth University
      • Department of Human and Molecular Genetics
      Richmond, VA, United States
  • 2008
    • Peking University Health Science Center
      Peping, Beijing, China