Browsing by Author "Jabeen, Rukhsana"

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    Altered STAT4 isoform expression in patients with inflammatory bowel disease.
    (Wolters Kluwer, 2015-10) Jabeen, Rukhsana; Miller, Lucy; Yao, Weiguo; Gupta, Sandeep; Steiner, Steven; Kaplan, Mark H.; Department of Pediatrics, IU School of Medicine
    BACKGROUND & AIMS: Crohn’s disease (CD) and ulcerative colitis (UC) are major forms of inflammatory bowel disease (IBD) and pathogenesis involves a complex interplay between genetic, environmental and immunological factors. We evaluated isoform expression of the IL-12-activated transcription factor STAT4 in children with CD and UC. METHODS: We performed a study where we collected biopsy samples from both newly diagnosed CD and UC patients. We further collected blood samples from newly diagnosed CD and UC patients as well as patients who had a flare-up after being in clinical remission, and examined the ratios of STAT4β/STAT4α mRNA. In addition to STAT4 isoforms we measured the expression of the cytokines TNFα, IFNγ, GM-CSF and IL-17 using PCR of biopsy samples and multiplex analysis of patient serum samples. RESULTS: Ratios of STAT4β/STAT4α were increased in specific GI tract segments in both CD and UC patients that correlate with location and severity of inflammation. In contrast, we did not observe changes in STAT4β/STAT4α ratios in biopsy specimens from eosinophilic esophagitis patients. We also observed increased STAT4β/STAT4α ratios in the peripheral blood mononuclear cells of UC and CD patients, compared to healthy controls. Ratios were normalized after patient treatment with steroids. CONCLUSIONS: Collectively, these data indicate that STAT4 isoforms could be an important non-invasive biomarker in the diagnosis and treatment of IBD, and that expression of these isoforms might provide further insight into the pathogenesis of IBD.
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    The ETS family transcription factors Etv5 and PU.1 function in parallel to promote Th9 cell development
    (American Association of Immunologists, 2016-09-15) Koh, Byunghee; Hufford, Matthew M; Pham, Duy; Olson, Matthew R.; Wu, Tong; Jabeen, Rukhsana; Sun, Xin; Kaplan, Mark H.; Microbiology and Immunology, School of Medicine
    The IL-9-secreting Th9 subset of CD4 T helper cells develop in response to an environment containing IL-4 and TGFβ, promoting allergic disease, autoimmunity, and resistance to pathogens. We previously identified a requirement for the ETS family transcription factor PU.1 in Th9 development. In this report we demonstrate that the ETS transcription factor ETV5 promotes IL-9 production in Th9 cells by binding and recruiting histone acetyltransferases to the Il9 locus at sites distinct from PU.1. In cells that are deficient in both PU.1 and ETV5 there is lower IL-9 production than in cells lacking either factor alone. In vivo loss of PU.1 and ETV5 in T cells results in distinct affects on allergic inflammation in the lung, suggesting that these factors function in parallel. Together, these data define a role for ETV5 in Th9 development and extend the paradigm of related transcription factors having complementary functions during differentiation.
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    PU.1 expression in T follicular helper cells limits CD40L-dependent germinal center B cell development.
    (American Association of Immunologists, 2015-10-15) Awe, Olufolakemi; Hufford, Matthew M.; Wu, Hao; Pham, Duy; Chang, Hua-Chen; Jabeen, Rukhsana; Dent, Alexander L.; Kaplan, Mark H.; Department of Microbiology and Immunology, IU School of Medicine
    PU.1 is an ETS family transcription factor important for the development of multiple hematopoietic cell lineages. Previous work demonstrated a critical role for PU.1 in promoting Th9 development, and in limiting Th2 cytokine production. Whether PU.1 has functions in other T helper lineages is not clear. In this report we examined the effects of ectopic expression of PU.1 in CD4+T cells and observed decreased expression of genes involved with the function of T follicular helper (Tfh) cells, including Il21 and Tnfsf5 (encoding CD40L). T cells from conditional mutant mice that lack expression of PU.1 in T cells (Sfpi1lck−/−) demonstrated increased production of CD40L and IL-21 in vitro. Following adjuvant-dependent or adjuvant-independent immunization, we observed that Sfpi1lck−/− mice had increased numbers of Tfh cells, increased germinal center B cells, and increased antibody production in vivo. This correlated with increased expression of IL-21 and CD40L in Tfh cells from Sfpi1lck−/− mice, compared to control mice. Finally, although blockade of IL-21 did not affect germinal center B cells in Sfpi1lck−/− mice, anti-CD40L treatment of immunized Sfpi1lck−/− mice decreased germinal center B cell numbers and antigen-specific immunoglobulin concentrations. Together, these data indicate an inhibitory role of PU.1 in the function of T follicular helper cells, germinal centers, and Tfh-dependent humoral immunity.
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    STAT4 deficiency reduces the development of atherosclerosis in mice
    (Elsevier, 2015-11) Taghavie-Moghadam, Parésa L.; Gjurich, Breanne N.; Jabeen, Rukhsana; Krishnamurthy, Purna; Kaplan, Mark H.; Dobrian, Anca D.; Nadler, Jerry L.; Galkina, Elena V.; Department of Pediatrics, IU School of Medicine
    Atherosclerosis is a chronic inflammatory process that leads to plaque formation in large and medium sized vessels. T helper 1 (Th1) cells constitute the majority of plaque infiltrating pro-atherogenic T cells and are induced via IFNγ-dependent activation of T-box (Tbet) and/or IL-12-dependent activation of signal transducer and activator of transcription 4 (STAT4). We thus aimed to define a role for STAT4 in atherosclerosis. STAT4-deficiency resulted in a ∼71% reduction (p < 0.001) in plaque burden in Stat4(-/-)Apoe(-/-) vs Apoe(-/-) mice fed chow diet and significantly attenuated atherosclerosis (∼31%, p < 0.01) in western diet fed Stat4(-/-)Apoe(-/-) mice. Surprisingly, reduced atherogenesis in Stat4(-/-)Apoe(-/-) mice was not due to attenuated IFNγ production in vivo by Th1 cells, suggesting an at least partially IFNγ-independent pro-atherogenic role of STAT4. STAT4 is expressed in T cells, but also detected in macrophages (MΦs). Stat4(-/-)Apoe(-/-)in vitro differentiated M1 or M2 MΦs had reduced cytokine production compare to Apoe(-/-) M1 and M2 MΦs that was accompanied by reduced induction of CD69, I-A(b), and CD86 in response to LPS stimulation. Stat4(-/-)Apoe(-/-) MΦs expressed attenuated levels of CCR2 and demonstrated reduced migration toward CCL2 in a transwell assay. Importantly, the percentage of aortic CD11b(+)F4/80(+)Ly6C(hi) MΦs was reduced in Stat4(-/-)Apoe(-/-) vs Apoe(-/-) mice. Thus, this study identifies for the first time a pro-atherogenic role of STAT4 that is at least partially independent of Th1 cell-derived IFNγ, and primarily involving the modulation of MΦ responses.