The transcription factor STAT5 is critical in dendritic cells for the development of TH2 but not TH1 responses

Bell, Bryan D.; Kitajima, Masayuki; Larson, Ryan; Stoklasek, Thomas A.; Dang, Kristen K.; Sakamoto, Kazuhiro; Wagner, Kay Uwe; Reizis, Boris; Hennighausen, Lothar; Ziegler, Steven F.

doi:10.1038/ni.2541

Cited by 174 publications

(171 citation statements)

References 48 publications

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“…CCL17 production, in turn, was shown previously to be inducible in certain DC subsets in vitro mainly by IL-4, IL-13, TNF, and GM-CSF [5,25,26,38]. Furthermore, Stat5 and Stat6 were identified as transcription factors, which induce CCL17 expression [25,39,40]. While we achieved only minimal stimulation of CCL17 production by incubation of splenic DCs with IL-13 (data not shown) and TNF (Fig.…”

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confidence: 50%

Cytokine‐dependent regulation of dendritic cell differentiation in the splenic microenvironment

et al. 2013

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The DC-derived chemokine CCL17, a ligand of CCR4, has been shown to promote various inflammatory diseases such as atopic dermatitis, atherosclerosis, and inflammatory bowel disease. Under steady-state conditions, and even after systemic stimulation with LPS, CCL17 is not expressed in resident splenic DCs as opposed to CD8α − CD11b + LN DCs, which produce large amounts of CCL17 in particular after maturation. Upon systemic NKT cell activation through α-galactosylceramide stimulation however, CCL17 can be upregulated in both CD8α − and CD8α + splenic DC subsets and enhances crosspresentation of exogenous antigens. Based on genome-wide expression profiling, we now show that splenic CD11b + DCs are susceptible to IFN-γ-mediated suppression of CCL17, whereas LN CD11b + CCL17 + DCs downregulate the IFN-γR and are much less responsive to IFN-γ. Under inflammatory conditions, particularly in the absence of IFN-γ signaling in IFN-γRKO mice, CCL17 expression is strongly induced in a major proportion of splenic DCs by the action of GM-CSF in concert with IL-4. Our findings demonstrate that the local cytokine milieu and differential cytokine responsiveness of DC subsets regulate lymphoid organ specific immune responses at the level of chemokine expression.Keywords: DCs r GM-CSF r IFN-γ receptor r IL-4 r Spleen Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionDCs are important sentinels of the immune system. Based on their developmental origin, surface phenotype, and mobility, DCs can be subdivided into several major subsets, such as plasmacytoid Correspondence: Prof. Irmgard Förster e-mail: irmgard.foerster@uni-bonn.deDCs, resident DCs of lymphoid organs, and migratory DC subsets, which are mainly found in nonlymphoid tissues and their local draining LN [1]. In the lamina propria of the gut and in MLN, CD103 + CD11b + DCs were identified as the major migratory DC subset with potency to induce both tolerance and immunity * These authors contributed equally to this work.C 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2014. 44: 500-510 Immunomodulation 501 [2,3]. In contrast to visceral and peripheral LN (PLN), the spleen harbors mainly lymphoid organ resident DCs with the exception of circulating plasmacytoid DCs [4]. Under inflammatory conditions monocytes are able to differentiate into mature DCs through the recognition of PAMPs in conjunction with GM-CSF (Csf-2) [5,6]. GM-CSF has been implicated in the formation of inflammatory DCs in vivo [7], and was also shown to enhance CD103 expression and the ability of CD8α + DCs to cross-present antigens to CD8 + T cells [8][9][10].Besides the classification of DC subsets on the basis of surface phenotype and migratory abilities, there is evidence that the local organ-specific microenvironment also has distinct influences on DC function even in phenotypically similar DC subsets. At the level of transcriptional profiling this has been indicated by direct comparison of...

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Cytokine‐dependent regulation of dendritic cell differentiation in the splenic microenvironment

et al. 2013

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“…The molecular mechanisms underlying the antiinflammatory effects of TSLP remain unclear. TSLP has been shown to induce signal transducer and activator of transcription (STAT) 1, STAT3, STAT4, STAT5, and STAT6 phosphorylation in human DCs, whereas it only activates STAT5 in mouse DCs (37,39 The down-regulatory effects of TSLP on inflammation may not be limited to its direct effects on myeloid cell function. Recent studies indicate that injury is associated with increased inflammation and worsens mortality in septic mice that do not express the transcription factor, NF-kB, in their intestinal epithelium (41).…”

Section: Discussionmentioning

confidence: 99%

Thymic Stromal Lymphopoietin Improves Survival and Reduces Inflammation in Sepsis

Piliponsky

Lahiri

Truong

et al. 2016

Am J Respir Cell Mol Biol

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The mechanisms that contribute to homeostasis of the immune system in sepsis are largely unknown. One study suggests a potential detrimental role for thymic stromal lymphopoietin (TSLP) in sepsis; however, the immune-regulatory effects of TSLP on myeloid cells within the intestinal microenvironment suggest the contrary. Our objective was to clarify TSLP's role in sepsis. Cecal ligation and puncture was performed in mice with total or myeloid-specific deficiency in the TSLP receptor (TSLPR). Survival was monitored closely, peritoneal fluids and plasma were analyzed for markers of inflammation, and myeloid cell numbers and their ability to produce inflammatory mediators was determined. The interaction of TSLP with TSLPR in myeloid cells contributed to mouse survival after septic peritonitis. Mice with TSLPR deficiency in myeloid cells displayed excessive local and systemic inflammation levels (e.g., increased inflammatory cell and cytokine levels) relative to control mice. Moreover, hepatic injury was exacerbated in mice with TSLPR deficiency in their myeloid cells. However, the enhanced inflammatory response did not affect the ability of these mice to clear bacteria. Resident neutrophils and macrophages from septic mice with TSLPR deficiency exhibited an increased ability to produce proinflammatory cytokines. Collectively, our findings suggest that the effects of TSLP on myeloid cells are crucial in reducing the multiple organ failure that is associated with systemic inflammation, which highlights the significance of this cytokine in modulating the host response to infection and in reducing the risks of sepsis development.Keywords: sepsis; inflammation; myeloid cells; thymic stromal lymphopoietin Clinical RelevanceInfections can lead to sepsis, a complex, incompletely understood, and often fatal disorder that is considered to reflect dysregulation of the host immune response. Early diagnosis and treatment of sepsis is critical to prevent the cascade of the complex processes that lead to severe sepsis and septic shock. However, the best available diagnostic and treatment strategies have failed, which underscores the need for a better understanding of the pathophysiological mechanisms regulating the inflammatory host response during sepsis. Our study provides evidence that thymic stromal lymphopoietin is part of a mechanism that is initiated by the host to restore homeostasis during the inflammatory response against bacterial infections to reduce the risk of sepsis development.

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“…We conclude that transcriptional activators other than C/EBPb could contribute to IGF-1 transcriptional regulation, depending on tumour-imposed stress conditions. Indeed, several other transcription factors were shown to activate IGF-1 transcription in diverse cell types, including Stat5 in hepatocytes and putatively in DCs [47][48][49] , C/EBPd in osteoblasts and putatively DCs 50 , and IRF8 in hepatocytes 51 . When IGF-1 and other potentially B-cell growth-promoting cytokines were tested in a DC-independent cell culture, gain of viability between the Em-Myc lymphoma B-cell clones varied substantially.…”

Section: Discussionmentioning

confidence: 99%

Dendritic cell-mediated survival signals in Eμ-Myc B-cell lymphoma depend on the transcription factor C/EBPβ

et al. 2014

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The capacity of dendritic cells (DCs) to regulate tumour-specific adaptive immune responses depends on their proper differentiation and homing status. Whereas DC-associated tumour-promoting functions are linked to T-cell tolerance and formation of an inflammatory milieu, DC-mediated direct effects on tumour growth have remained unexplored. Here we show that deletion of DCs substantially delays progression of Myc-driven lymphomas. Lymphoma-exposed DCs upregulate immunomodulatory cytokines, growth factors and the CCAAT/enhancer-binding protein b (C/EBPb). Moreover, Em-Myc lymphomas induce the preferential translation of the LAP/LAP* isoforms of C/EBPb. C/EBPb À/ À DCs are unresponsive to lymphoma-associated cytokine changes and in contrast to wild-type DCs, they are unable to mediate enhanced Em-Myc lymphoma cell survival. Antigen-specific T-cell proliferation in lymphoma-bearing mice is impaired; however, this immune suppression is reverted by the DC-restricted deletion of C/EBPb. Thus, we show that C/EBPb-controlled DC functions are critical steps for the creation of a lymphoma growth-promoting and -immunosuppressive niche.

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The transcription factor STAT5 is critical in dendritic cells for the development of TH2 but not TH1 responses

Cited by 174 publications

References 48 publications

Cytokine‐dependent regulation of dendritic cell differentiation in the splenic microenvironment

Cytokine‐dependent regulation of dendritic cell differentiation in the splenic microenvironment

Thymic Stromal Lymphopoietin Improves Survival and Reduces Inflammation in Sepsis

Dendritic cell-mediated survival signals in Eμ-Myc B-cell lymphoma depend on the transcription factor C/EBPβ

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