Interleukin-17 Promotes Autoimmunity by Triggering a Positive-Feedback Loop via Interleukin-6 Induction

Ogura, Hideki; Murakami, Masaaki; Okuyama, Yuko; Tsuruoka, Mineko; Kitabayashi, Chika; Kanamoto, Minoru; Nishihara, Masateru; Iwakura, Yoichiro; Hirano, Toshio

doi:10.1016/j.immuni.2008.07.018

Cited by 509 publications

(495 citation statements)

References 61 publications

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“…Since some ILs including IL1b and IL6 are transcriptionally regulated by NF-kB, which may create a positive feedback loop to chronically activate the signaling pathway [36,37], we further tested whether IL1b and IL6 could be self-regulated via the NF-kB signaling. Interestingly, the attenuation of NF-kB suppressed the expressions of IL1b and IL6 at both mRNA and protein levels in the supernatant ( Supplementary Fig.…”

Section: Il1b and Il6 Served As The Nf-jb Signaling Potential Regulatmentioning

confidence: 99%

Transcriptional Profiling Reveals Crosstalk Between Mesenchymal Stem Cells and Endothelial Cells Promoting Prevascularization by Reciprocal Mechanisms

LiJunxiang

MaYing

TengRuifang

et al. 2015

Stem Cells and Development

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Mesenchymal stem cells (MSCs) show great promise in blood vessel restoration and vascularization enhancement in many therapeutic situations. Typically, the co-implantation of MSCs with vascular endothelial cells (ECs) is effective for the induction of functional vascularization in vivo, indicating its potential applications in regenerative medicine. The effects of MSCs-ECs-induced vascularization can be modeled in vitro, providing simplified models for understanding their underlying communication. In this article, a contact coculture model in vitro and an RNA-seq approach were employed to reveal the active crosstalk between MSCs and ECs within a short time period at both morphological and transcriptional levels. The RNA-seq results suggested that angiogenic genes were significantly induced upon coculture, and this prevascularization commitment might require the NF-kB signaling. NF-kB blocking and interleukin (IL) neutralization experiments demonstrated that MSCs potentially secreted IL factors including IL1b and IL6 to modulate NF-kB signaling and downstream chemokines during coculture. Conversely, RNA-seq results indicated that the MSCs were regulated by the coculture environment to a smooth muscle commitment within this short period, which largely induced myocardin, the myogenic co-transcriptional factor. These findings demonstrate the mutual molecular mechanism of MSCs-ECs-induced prevascularization commitment in a quick response.

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Section: Il1b and Il6 Served As The Nf-jb Signaling Potential Regulatmentioning

confidence: 99%

Transcriptional Profiling Reveals Crosstalk Between Mesenchymal Stem Cells and Endothelial Cells Promoting Prevascularization by Reciprocal Mechanisms

LiJunxiang

MaYing

TengRuifang

et al. 2015

Stem Cells and Development

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“…In addition to its effects on antibody production, IL-6 has a strong stimulatory effect on the growth of mouse plasmacytoma [13] and human myeloma cells [12]. Recently, Ogura et al [14] have reported that IL-17 promotes autoimmunity by triggering a positive-feedback loop through the induction of IL-6. In the study reported herein, we generated transgenic (Tg) mice that overexpressed RORγt and showed that RORγt Tg mice displayed excessive IL-6 production, the development of plasmacytosis, and autoantibody production.…”

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confidence: 99%

Overexpression of RORγt under control of the CD2 promoter induces polyclonal plasmacytosis and autoantibody production in transgenic mice

et al. 2012

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Retinoic acid related orphan receptor gamma-t (RORγt) is known to be a master regulator of Th17-cell development. In this study, we generated RORγt-overexpressing transgenic (RORγt Tg) mice in which transgene expression was driven by the CD2 promoter, and found that these mice developed polyclonal plasmacytosis and autoantibody production. RORγt Tg mice were generated on a C57BL/6 background, and also were intercrossed with BALB/c mice. BALB/c F1 (BALB/F1) RORγt Tg mice developed massive polyclonal plasmacytosis, and had shorter life spans. Splenomegaly and infiltration of plasma cells into the lung were observed. Hyperglobulinemia, anti-double-stranded DNA antibodies, antierythrocyte antibodies, and anti-platelet antibodies were detected in BALB/F1 RORγt Tg mice. In the present study, polyclonal plasmacytosis in BALB/F1 RORγt Tg mice appeared to be due to the induction of excessive IL-6 production by IL-17. We detected increased numbers of CD11b + cells that produced IL-6. We also generated IL-6-deficient RORγt Tg BALB/F1 background mice, which displayed high levels of serum IL-17, but did not develop severe hyperglobulinemia. Excessive IL-6 production by several cell types, including macrophages, in BALB/F1 RORγt Tg mice, might effect the development of plasmacytosis. These results suggest that RORγt plays important roles in the development of plasmacytosis and autoantibody production. Eur. J. Immunol. 2012Immunol. . 42: 1999Immunol. -2009 Introduction CD4 + T helper (Th) cells are a subcategory of T lymphocytes that play a central role in modulating immune responses. Classically, naïve CD4 + T cells have been thought to differentiate into two cell types, Th1 and Th2 cells. This corresponds to the Th1/Th2 paradigm proposed by Mosmann et al. [1]. More recently, a third subset of Th cells, Th17 cells, has been described; this is a distinct lineage that does not share developmental pathways with either Th1 or Th2 cells [2,3]. Th17 cells are generally thought to be proinflammatory, especially through the production of 3]. Th17 cells have been shown to participate in the development of autoimmunity, and also to play an important role in host defense against infection [4]. Expression of the transcription factor retinoic acid related orphan receptor gamma-t (RORγt) is required for the differentiation of Th17 cells [5,6]. The orphan receptor RORγt is a thymusspecific isoform of RORγ [7]. A related nuclear receptor, RORα, was shown to act in synergy with RORγt to promote the differentiation of Th17 cells [8]. STAT3 is also required for full generation of the Th17 lineage [9]. The upregulation of RORγt depends on STAT3 [9], and the selective deletion of STAT3 in T cells partially abrogates the development of Th17 cells because it also abrogates the expression of RORα and RORγt [8].IL-6 is an important cytokine in the differentiation of Th17 cells. IL-6, together with TGF-β, is required to induce IL-17 expression in naïve CD4 + T cells, which are characterized by the expression of RORγt [5,10,11]. Since its discovery i...

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“…One mechanism associated with this development and specific to nonimmune cells, such as synovial cells, fibroblasts, and endothelial cells, is an NF-kB activator, the inflammation amplifier (formerly IL-6 amplifier) (15), which is activated by a simultaneous stimulation of NF-kB and STAT3. The main functional molecules of the inflammation amplifier are chemokines and growth factors, which deregulate local homeostasis via an accumulation of various immune cells and proliferate various regional cells, whereas IL-6 mainly acts as fuel to maintain the activation of STAT3 (16,17).…”

Section: B Reakpoint Cluster Region (Bcr) Protein Is a Unique Kinasementioning

confidence: 99%

“…We previously reported an inflammation-inducing mechanism, called the inflammation amplifier, in nonimmune cells such as synovial cells and endothelial cells (15), which is activated by a simultaneous stimulation of NF-kB and STAT3 and involved in the pathogenesis of several inflammatory disease models (17)(18)(19). By genome-wide screenings, we have identified that BCR is one of the positive regulators of the inflammation amplifier (17).…”

Section: Bcr Is Critical For Nf-kb Activation In Vivo and In Vitromentioning

confidence: 99%

Breakpoint Cluster Region–Mediated Inflammation Is Dependent on Casein Kinase II

Meng

Jiang

Atsumi

et al. 2016

The Journal of Immunology

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The breakpoint cluster region (BCR) is known as a kinase and cause of leukemia upon fusing to Abl kinase. In this study, we demonstrate that BCR associated with the α subunit of casein kinase II (CK2α), rather than BCR itself, is required for inflammation development. We found that BCR knockdown inhibited NF-κB activation in vitro and in vivo. Computer simulation, however, suggested that the putative BCR kinase domain has an unstable structure with minimal enzymatic activity. Liquid chromatography–tandem mass spectrometry analysis showed that CK2α associated with BCR. We found the BCR functions are mediated by CK2α. Indeed, CK2α associated with adaptor molecules of TNF-αR and phosphorylated BCR at Y177 to establish a p65 binding site after TNF-α stimulation. Notably, p65 S529 phosphorylation by CK2α creates a p300 binding site and increased p65-mediated transcription followed by inflammation development in vivo. These results suggest that BCR-mediated inflammation is dependent on CK2α, and the BCR–CK2α complex could be a novel therapeutic target for various inflammatory diseases.

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Interleukin-17 Promotes Autoimmunity by Triggering a Positive-Feedback Loop via Interleukin-6 Induction

Cited by 509 publications

References 61 publications

Transcriptional Profiling Reveals Crosstalk Between Mesenchymal Stem Cells and Endothelial Cells Promoting Prevascularization by Reciprocal Mechanisms

Transcriptional Profiling Reveals Crosstalk Between Mesenchymal Stem Cells and Endothelial Cells Promoting Prevascularization by Reciprocal Mechanisms

Overexpression of RORγt under control of the CD2 promoter induces polyclonal plasmacytosis and autoantibody production in transgenic mice

Breakpoint Cluster Region–Mediated Inflammation Is Dependent on Casein Kinase II

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