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


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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    • "In addition to its role in cytokine signaling, STAT3 is also activated downstream of several chemokine receptors [16] [17]. Importantly our group has shown that siRNA-mediated knockdown of STAT3 in vitro inhibited SLE T cell migration [5]. Because STAT3 is crucial for T cells to provide B cell help, the development of pathogenic Th17 cells and T cell migration, we sought to determine the effects of inhibiting this pathway both in vitro and in vivo. "
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    ABSTRACT: The transcription factor STAT3 is overexpressed and hyperactivated in T cells from SLE patients . STAT3 plays a central role in T cell differentiation into Th17 and T follicular helper cells, two subsets that orchestrate autoimmune responses in SLE. Moreover, STAT3 is important in chemokine-mediated T cell migration. To better understand its role in SLE, we inhibited STAT3 in lupus-prone mice using the small molecule Stattic. Stattic-treated mice exhibited delayed onset of proteinuria (3 weeks later than controls), and had lower levels of anti-dsDNA antibodies and inflammatory cytokines. Inhibitor treatment reduced lymphadenopathy, resulted in a 3-fold decrease in total T cell number, and a 4-fold decrease in the numbers of T follicular helper cells. In vitro experiments showed that Stattic-treated T cells exhibited decreased proliferation and a decrease in ability to migrate to CXCL12. We propose that STAT3 inhibition represents a therapeutic target in SLE, particularly lupus nephritis. Copyright © 2015. Published by Elsevier Inc.
    Full-text · Article · Apr 2015 · Clinical Immunology
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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.
    Full-text · Article · Jun 2013 · PLoS ONE
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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.
    Full-text · Article · May 2013 · PLoS ONE
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