Xiao Mei Wang

University of Florida, Gainesville, FL, United States

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Publications (9)45.78 Total impact

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    ABSTRACT: Toll-like receptors (TLRs) exert important non-immune functions in lung homeostasis. TLR4 deficiency promotes pulmonary emphysema. We examined the role of TLR4 in regulating cigarette smoke (CS)-induced autophagy, apoptosis, and emphysema. Lung tissue was obtained from chronic obstructive lung disease (COPD) patients. C3H/HeJ (Tlr4-mutated) mice and C57BL/10ScNJ (Tlr4-deficient) mice, and their respective control strains were exposed to chronic CS or air. Human or mouse epithelial cells (wild type, Tlr4-knockdown, and Tlr4-deficient) were exposed to CS-extract (CSE). Samples were analyzed for TLR4 expression, and for autophagic or apoptotic proteins by Western analysis or confocal imaging. COPD lung tissues, and human pulmonary epithelial cells exposed to CSE displayed increased TLR4 expression, and increased autophagic (microtubule-associated protein 1 light chain-3B, LC3B) and apoptotic (cleaved caspase-3) markers. Beas-2B cells transfected with TLR4 siRNA displayed increased expression of LC3B relative to control cells, basally and after exposure to CSE. The basal and CSE-inducible expression of LC3B and cleaved caspase-3 were elevated in pulmonary alveolar type II (ATII) cells from Tlr4-deficient mice. Wild-type mice subjected to chronic CS-exposure displayed airspace enlargement, however, the Tlr4-mutated or Tlr4-deficient mice exhibited a marked increase in airspace relative to wild-type mice after CS-exposure. The Tlr4-mutated or Tlr4-deficient mice showed higher levels of LC3B under basal conditions and after CS-exposure. The expression of cleaved caspase-3 was markedly increased in Tlr4-deficient mice exposed to CS. We describe a protective regulatory function of TLR4 against emphysematous changes of the lung in response to CS.
    AJP Lung Cellular and Molecular Physiology 09/2012; · 3.52 Impact Factor
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    ABSTRACT: Caveolin 1 (Cav-1), the scaffold protein of a specific membrane lipid raft called caveolae, has been reported to suppress HIV-1 replication. However, the mechanism by which Cav-1 inhibits HIV replication remains unclear. In this study, we investigated the mechanism by which Cav-1 inhibits HIV replication at the level of gene expression. Our results show that Cav-1 represses viral gene expression and that this suppression involves the NF-κB pathway. We used several approaches in different cell types, including primary CD4(+) T cells and macrophages, to demonstrate the role of nuclear factor κB (NF-κB) in Cav-1-mediated inhibition of viral expression. A mutational analysis of the cis-acting element shows that the two NF-κB sites in the U3 region of the long terminal repeat (LTR) are critical for Cav-1-mediated inhibition of viral expression. In the presence of Cav-1, phosphorylation of IKKβ, IKKα, IκBα, and NF-κB p65 is dramatically reduced, while viral gene expression is suppressed. In addition, translocation of NF-κB p65 to the nucleus decreases substantially in the presence of Cav-1. Furthermore, significant inhibition of NF-κB activation and binding to target DNA are evident in the presence of Cav-1. These results establish evidence that Cav-1 inhibits HIV replication by transcriptional repression of viral gene expression and contributes to HIV's persistent infection of macrophages.
    Journal of Virology 03/2011; 85(11):5483-93. · 5.08 Impact Factor
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    ABSTRACT: Caveolin 1 (Cav-1) is a major protein of a specific membrane lipid raft known as caveolae. Cav-1 interacts with the gp41 of the human immunodeficiency virus (HIV) envelope, but the role of Cav-1 in HIV replication and pathogenesis is not known. In this report, we demonstrate that HIV infection in primary human monocyte-derived macrophages (MDMs), THP-1 macrophages, and U87-CD4 cells results in a dramatic upregulation of Cav-1 expression mediated by HIV Tat. The activity of p53 is essential for Tat-induced Cav-1 expression, as our findings show enhanced phosphorylation of serine residues at amino acid positions 15 and 46 in the presence of Tat with a resulting Cav-1 upregulation. Furthermore, inhibition of p38 mitogen-activated protein kinase (MAPK) blocked phosphorylation of p53 in the presence of Tat. Infection studies of Cav-1-overexpressing cells reveal a significant reduction of HIV production. Taken together, these results suggest that HIV infection enhances the expression of Cav-1, which subsequently causes virus reduction, suggesting that Cav-1 may contribute to persistent infection in macrophages.
    Journal of Virology 09/2010; 84(18):9487-96. · 5.08 Impact Factor
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    ABSTRACT: Human immunodeficiency virus (HIV) envelope (Env)-mediated bystander apoptosis is known to cause the progressive, severe, and irreversible loss of CD4(+) T cells in HIV-1-infected patients. Env-induced bystander apoptosis has been shown to be gp41 dependent and related to the membrane hemifusion between envelope-expressing cells and target cells. Caveolin-1 (Cav-1), the scaffold protein of specific membrane lipid rafts called caveolae, has been reported to interact with gp41. However, the underlying pathological or physiological meaning of this robust interaction remains unclear. In this report, we examine the interaction of cellular Cav-1 and HIV gp41 within the lipid rafts and show that Cav-1 modulates Env-induced bystander apoptosis through interactions with gp41 in SupT1 cells and CD4(+) T lymphocytes isolated from human peripheral blood. Cav-1 significantly suppressed Env-induced membrane hemifusion and caspase-3 activation and augmented Hsp70 upregulation. Moreover, a peptide containing the Cav-1 scaffold domain sequence markedly inhibited bystander apoptosis and apoptotic signal pathways. Our studies shed new light on the potential role of Cav-1 in limiting HIV pathogenesis and the development of a novel therapeutic strategy in treating HIV-1-infected patients.
    Journal of Virology 07/2010; 84(13):6515-26. · 5.08 Impact Factor
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    ABSTRACT: Caveolin-1 (cav-1), the principle structural protein of plasmalemmal caveolae, regulates inflammatory signaling processes originating at the membrane. We show that cav-1 bound to TLR4 and inhibited LPS-induced proinflammatory cytokine (TNF-alpha and IL-6) production in murine macrophages. Mutation analysis revealed a cav-1 binding motif in TLR4, essential for this interaction and for attenuation of proinflammatory signaling. Cav-1 was required for the anti-inflammatory effects of carbon monoxide (CO), a product of heme oxygenase-1 (HO-1) activity. CO augmented the cav-1/TLR4 interaction. Upon LPS stimulation, HO-1 trafficked to the caveolae by a p38 MAPK-dependent mechanism, where it down-regulated proinflammatory signaling. These results reveal an anti-inflammatory network involving cav-1 and HO-1.
    The Journal of Immunology 04/2009; 182(6):3809-18. · 5.52 Impact Factor
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    ABSTRACT: Idiopathic pulmonary fibrosis (IPF) is a progressive chronic disorder characterized by activation of fibroblasts and overproduction of extracellular matrix (ECM). Caveolin-1 (cav-1), a principal component of caveolae, has been implicated in the regulation of numerous signaling pathways and biological processes. We observed marked reduction of cav-1 expression in lung tissues and in primary pulmonary fibroblasts from IPF patients compared with controls. We also demonstrated that cav-1 markedly ameliorated bleomycin (BLM)-induced pulmonary fibrosis, as indicated by histological analysis, hydroxyproline content, and immunoblot analysis. Additionally, transforming growth factor beta1 (TGF-beta1), the well-known profibrotic cytokine, decreased cav-1 expression in human pulmonary fibroblasts. cav-1 was able to suppress TGF-beta1-induced ECM production in cultured fibroblasts through the regulation of the c-Jun N-terminal kinase (JNK) pathway. Interestingly, highly activated JNK was detected in IPF- and BLM-instilled lung tissue samples, which was dramatically suppressed by ad-cav-1 infection. Moreover, JNK1-null fibroblasts showed reduced smad signaling cascades, mimicking the effects of cav-1. This study indicates a pivotal role for cav-1 in ECM regulation and suggests a novel therapeutic target for patients with pulmonary fibrosis.
    Journal of Experimental Medicine 01/2007; 203(13):2895-906. · 13.21 Impact Factor
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    ABSTRACT: Cyclooxygenase-2 (COX-2) is a key enzyme involved in the inflammatory process that is rapidly induced in macrophages in response to LPS. Carbon monoxide (CO), a byproduct of heme oxygnease-1, can suppress proinflammatory response in various in vitro and in vivo models of inflammation. This study was undertaken to examine whether CO can regulate (and if so, to delineate the mechanism by which CO regulates) LPS-induced COX-2 expression in macrophages. RAW 264.7 murine macrophages were stimulated with LPS (0-10 ng/ml) with or without CO (500 ppm). Northern and Western blot analysis was done. Progstaglandin E(2) and nitrite concentration was measured from cell culture supernatant. Electrophoretic mobility shift assay was performed to assess nuclear factor binding. CO downregulated LPS-induced COX-2 mRNA and protein expression. CO also inhibited LPS-induced prostaglandin E(2) secretion (P < 0.05). CO also decreased LPS-induced CCAAT/enhancer-binding protein (C/EBP) beta and delta protein expression in LPS-treated RAW 264.7 cells. Gel shift analysis revealed that CO treatment decreased LPS-induced activation of protein binding to C/EBP consensus oligonucleotides of murine cyclooxygenase-2 promoter. CO also decreased LPS-induced nitric oxide synthase-2 protein expression and nitrite production, and decreased LPS-induced activation of protein binding to C/EBP consensus oligonucleotides of murine nitric oxide synthase-2 promoter. CO may act as an important regulator of inflammation by virtue of its ability to regulate C/EBPs.
    American Journal of Respiratory Cell and Molecular Biology 08/2006; 35(2):220-6. · 4.15 Impact Factor
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    ABSTRACT: Caveolin-1 has been reported to regulate apoptosis, lipid metabolism, and endocytosis in macrophages. In the present study, we demonstrate that caveolin-1 can act as a potent immunomodulatory molecule. We first observed caveolin-1 expression in murine alveolar macrophages by Western blotting and immunofluorescence microscopy. Loss-of-function experiments using small interfering RNA showed that down regulating caveolin-1 expression in murine alveolar and peritoneal macrophages increased LPS-induced proinflammatory cytokine TNF-alpha and IL-6 production but decreased anti-inflammatory cytokine IL-10 production. Gain-of-function experiments demonstrated that overexpression of caveolin-1 in RAW264.7 cells decreased LPS-induced TNF-alpha and IL-6 production and augmented IL-10 production. p38 mitogen-activated protein kinase (MAPK) phosphorylation was increased by overexpressing caveolin-1 in RAW264.7 cells, whereas c-Jun N-terminal kinase, extracellular signal-regulated kinase MAPK, and Akt phosphorylation were inhibited. The antiinflammatory modulation of LPS-induced cytokine production by caveolin-1 was significantly abrogated by the administration of p38 inhibitor SB203580 in RAW264.7 cells. Peritoneal macrophages isolated from MKK3 null mice did not demonstrate any modulation of LPS-induced cytokine production by caveolin-1. LPS-induced activation of NF-kappaB and AP-1 determined by electrophoretic mobility shift assay were significantly reduced by overexpressing caveolin-1 in RAW264.7 cells. The reductions were attenuated by the administration of p38 inhibitor SB203580. Taken together, our data suggest that caveolin-1 acts as a potent immunomodulatory effector molecule in immune cells and that the regulation of LPS-induced cytokine production by caveolin-1 involves the MKK3/p38 MAPK pathway.
    American Journal of Respiratory Cell and Molecular Biology 05/2006; 34(4):434-42. · 4.15 Impact Factor
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    Xiao Mei Wang

Publication Stats

327 Citations
45.78 Total Impact Points

Institutions

  • 2010–2011
    • University of Florida
      • Department of Infectious Diseases and Pathology
      Gainesville, FL, United States
  • 2006–2009
    • University of Pittsburgh
      • • School of Medicine
      • • Department of Critical Care Medicine
      • • Department of Medicine
      Pittsburgh, PA, United States