Increased expression of STAT3 in SLE T cells contributes to enhanced chemokine-mediated cell migration

Harvard University, Cambridge, Massachusetts, United States
Autoimmunity (Impact Factor: 2.71). 03/2007; 40(1):1-8. DOI: 10.1080/08916930601095148
Source: PubMed

ABSTRACT Exposure of T cells to inflammatory cytokines leads to phosphorylation-dependent activation of signal transducer and activator of transcription (STAT) 3. T cells from patients with systemic lupus erythematosus (SLE) display increased levels of total and phosphorylated STAT3 which resides primarily in the nucleus. Increased STAT3 is associated with increased expression of target genes. Silencing of STAT3 expression using a small interfering RNA approach resulted in decreased chemokine-provoked SLE T cell migration. Our data suggest that inhibition of STAT3 expression may reverse the signaling aberrations involved in SLE T cell migration.

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    • "SGK1 has recently been shown to be a key regulator of pathogenic autoreactive Th17 cells [61], [62]. Our findings support previous studies describing the aberrant activation state of peripheral blood SLE T cells [63]–[66]. We noted the robust expression of certain IFN-inducible transcripts in response to IFN-α stimulation [67]. "
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    ABSTRACT: Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that is characterized by defective immune tolerance combined with immune cell hyperactivity resulting in the production of pathogenic autoantibodies. Previous gene expression studies employing whole blood or peripheral blood mononuclear cells (PBMC) have demonstrated that a majority of patients with active disease have increased expression of type I interferon (IFN) inducible transcripts known as the IFN signature. The goal of the current study was to assess the gene expression profiles of isolated leukocyte subsets obtained from SLE patients. Subsets including CD19(+) B lymphocytes, CD3(+)CD4(+) T lymphocytes and CD33(+) myeloid cells were simultaneously sorted from PBMC. The SLE transcriptomes were assessed for differentially expressed genes as compared to healthy controls. SLE CD33(+) myeloid cells exhibited the greatest number of differentially expressed genes at 208 transcripts, SLE B cells expressed 174 transcripts and SLE CD3(+)CD4(+) T cells expressed 92 transcripts. Only 4.4% (21) of the 474 total transcripts, many associated with the IFN signature, were shared by all three subsets. Transcriptional profiles translated into increased protein expression for CD38, CD63, CD107a and CD169. Moreover, these studies demonstrated that both SLE lymphoid and myeloid subsets expressed elevated transcripts for cytosolic RNA and DNA sensors and downstream effectors mediating IFN and cytokine production. Prolonged upregulation of nucleic acid sensing pathways could modulate immune effector functions and initiate or contribute to the systemic inflammation observed in SLE.
    PLoS ONE 06/2013; 8(6):e67003. DOI:10.1371/journal.pone.0067003 · 3.23 Impact Factor
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    • "STAT3 activation has been linked to several autoimmune diseases, including systemic lupus erythematosus, a condition arising from uncontrolled humoral immune responses [47]–[49]. Conversely, STAT3 activation is absent in diseases characterized by poor humoral immune responses such as hyper IgE syndrome [50]. Furthermore, B cell Stat3-deficient mice fail to mount antigen-specific T cell-dependent IgG responses [51], suggesting a complex regulation between B cell-mediated humoral immunity and STAT3. "
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    ABSTRACT: The role of B cells in cancer and the underlying mechanisms remain to be further explored. Here, we show that tumor-associated B cells with activated STAT3 contribute to tumor development by promoting tumor angiogenesis. B cells with or without Stat3 have opposite effects on tumor growth and tumor angiogenesis in both B16 melanoma and Lewis Lung Cancer mouse models. Ex vivo angiogenesis assays show that B cell-mediated tumor angiogenesis is mainly dependent on the induction of pro-angiogenic gene expression, which requires Stat3 signaling in B cells. Furthermore, B cells with activated STAT3 are mainly found in or near tumor vasculature and correlate significantly with overall STAT3 activity in human tumors. Moreover, the density of B cells in human tumor tissues correlates significantly with expression levels of several STAT3-downstream pro-angiogenic genes, as well as the degree of tumor angiogenesis. Together, these findings define a novel role of B cells in promoting tumor progression through angiogenesis and identify STAT3 in B cells as potential therapeutic target for anti-angiogenesis therapy.
    PLoS ONE 05/2013; 8(5):e64159. DOI:10.1371/journal.pone.0064159 · 3.23 Impact Factor
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    • "In addition to increased levels of pro-inflammatory cytokines , increased production of IL-17 has also been attributed to the reduced IL-2 production observed in SLE. IL-2 is necessary for Treg cell maintenance but has been shown to hinder Il17a expression and Th17 differentiation (Harada and others 2007; "
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    ABSTRACT: Systemic lupus erythematosus (SLE) is an autoimmune disease associated with chronic immune activation and tissue damage. Organ damage in SLE results from the deposition of immune complexes and the infiltration of activated T cells into susceptible organs. Cytokines are intimately involved in every step of the SLE pathogenesis. Defective immune regulation and uncontrolled lymphocyte activation, as well as increased antigen presenting cell maturation are all influenced by cytokines. Moreover, expansion of local immune responses as well as tissue infiltration by pathogenic cells is instigated by cytokines. In this review, we describe the main cytokine abnormalities reported in SLE and discuss the mechanisms that drive their aberrant production as well as the pathogenic pathways that their presence promotes.
    Journal of interferon & cytokine research: the official journal of the International Society for Interferon and Cytokine Research 08/2011; 31(10):769-79. DOI:10.1089/jir.2011.0029 · 2.00 Impact Factor
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