Magnolol Attenuates Concanavalin A-induced Hepatic Fibrosis, Inhibits CD4+ T Helper 17 (Th17) Cell Differentiation and Suppresses Hepatic Stellate Cell Activation: Blockade of Smad3/Smad4 Signalling

2017 ◽  
Vol 120 (6) ◽  
pp. 560-570 ◽  
Author(s):  
Hongjun Zhang ◽  
Baoling Ju ◽  
Xiaoli Zhang ◽  
Yanfei Zhu ◽  
Ying Nie ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Hepatic Fibrosis ◽  
Hepatic Stellate Cell ◽  
Concanavalin A ◽  
Th17 Cell ◽  
Cell Activation ◽  
Stellate Cell ◽  
T Helper ◽  
T Helper 17 ◽  
Th17 Cell Differentiation

scholarly journals BET N-terminal bromodomain inhibition selectively blocks Th17 cell differentiation and ameliorates colitis in mice

2017 ◽  
Vol 114 (11) ◽  
pp. 2952-2957 ◽  
Author(s):  
Kalung Cheung ◽  
Geming Lu ◽  
Rajal Sharma ◽  
Adam Vincek ◽  
Ruihua Zhang ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Rna Polymerase Ii ◽  
Th17 Cell ◽  
Therapeutic Potential ◽  
Th2 Cells ◽  
Immune Functions ◽  
T Helper ◽  
T Helper 17 ◽  
Inflammatory Disorders ◽  
Th17 Cell Differentiation

T-helper 17 (Th17) cells have important functions in adaptor immunity and have also been implicated in inflammatory disorders. The bromodomain and extraterminal domain (BET) family proteins regulate gene transcription during lineage-specific differentiation of naïve CD4+ T cells to produce mature T-helper cells. Inhibition of acetyl-lysine binding of the BET proteins by pan-BET bromodomain (BrD) inhibitors, such as JQ1, broadly affects differentiation of Th17, Th1, and Th2 cells that have distinct immune functions, thus limiting their therapeutic potential. Whether these BET proteins represent viable new epigenetic drug targets for inflammatory disorders has remained an unanswered question. In this study, we report that selective inhibition of the first bromodomain of BET proteins with our newly designed small molecule MS402 inhibits primarily Th17 cell differentiation with a little or almost no effect on Th1 or Th2 and Treg cells. MS402 preferentially renders Brd4 binding to Th17 signature gene loci over those of housekeeping genes and reduces Brd4 recruitment of p-TEFb to phosphorylate and activate RNA polymerase II for transcription elongation. We further show that MS402 prevents and ameliorates T-cell transfer-induced colitis in mice by blocking Th17 cell overdevelopment. Thus, selective pharmacological modulation of individual bromodomains likely represents a strategy for treatment of inflammatory bowel diseases.

scholarly journals RORα enforces stability of the T-helper-17 cell effector program

2020 ◽  
Author(s):  
June-Yong Lee ◽  
Jason A. Hall ◽  
Maria Pokrovskii ◽  
Lina Kroehling ◽  
Lin Wu ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Th17 Cell ◽  
Th17 Cells ◽  
T Helper ◽  
T Helper 17 ◽  
Enhancer Element ◽  
Peripheral Tissues ◽  
Th17 Cell Differentiation

SummaryT helper 17 (Th17) cells regulate mucosal barrier defenses, but also promote multiple autoinflammatory diseases. Although many molecular determinants of Th17 cell differentiation have been described, the transcriptional programs that sustain Th17 cells in vivo remain obscure. The transcription factor RORγt is critical for Th17 cell differentiation, but a distinct role of the closely-related RORα, which is co-expressed in Th17 cells, is not known. Here we demonstrate that, although dispensable for Th17 cell differentiation, RORα governs optimal Th17 responses in peripheral tissues. Thus, the absence of RORα in T cells led to significant reductions in both RORγt expression and effector function amongst Th17 cells, due to need for cooperative RORα and RORγt binding to a newly-identified Rorc enhancer element that is essential for Th17 lineage maintenance in vivo. Altogether, these data point to a non-redundant role of RORα in Th17 lineage maintenance via reinforcement of the RORγt transcriptional program.

scholarly journals Complement promotes the development of inflammatory T-helper 17 cells through synergistic interaction with Toll-like receptor signaling and interleukin-6 production

Blood ◽  
2009 ◽  
Vol 114 (5) ◽  
pp. 1005-1015 ◽  
Author(s):  
Chongyun Fang ◽  
Xinhua Zhang ◽  
Takashi Miwa ◽  
Wen-Chao Song
Keyword(s):  
Cell Differentiation ◽  
Th17 Cell ◽  
Transfer Model ◽  
T Helper ◽  
T Helper 17 ◽  
C5a Receptor ◽  
Serum Factors ◽  
Th17 Cell Differentiation

Toll-like receptors (TLRs) and complement are 2 major components of innate immunity that provide a first-line host defense and shape the adaptive immune responses. We show here that coincidental activation of complement and several TLRs in mice led to the synergistic production of serum factors that promoted T-helper cell 17 (Th17) differentiation from anti-CD3/CD28 or antigen-stimulated T cells. Although multiple TLR-triggered cytokines were regulated by complement, Th17 cell–promoting activity in the serum was correlated with interleukin (IL)–6 induction, and antibody neutralization of IL-6 abrogated the complement effect. By using both in vitro and in vivo approaches, we examined in more detail the mechanism and physiologic implication of complement/TLR4 interaction on Th17-cell differentiation. We found that the complement effect required C5a receptor, was evident at physiologically relevant levels of C5a, and could be demonstrated in cultured peritoneal macrophages as well as in the setting of antigen immunization. Importantly, despite an inhibitory effect of complement on IL-23 production, complement-promoted Th17 cells were functionally competent in causing autoimmunity in an adoptive transfer model of experimental autoimmune encephalomyelitis. Collectively, these data establish a link between complement/TLR interaction and Th17-cell differentiation and provide new insight into the mechanism of action of complement in autoimmunity.

scholarly journals miRNAs Alter T Helper 17 Cell Fate in the Pathogenesis of Autoimmune Diseases

2021 ◽  
Vol 12 ◽  
Author(s):  
Junxia Huang ◽  
Xinzhi Xu ◽  
Ji Yang
Keyword(s):  
Immune Response ◽  
Cell Differentiation ◽  
Autoimmune Diseases ◽  
Cell Fate ◽  
Th17 Cell ◽  
Th17 Cells ◽  
T Helper ◽  
T Helper 17 ◽  
Th17 Cell Differentiation ◽  
And Function

T helper 17 (Th17) cells are characterized by the secretion of the IL-17 cytokine and are essential for the immune response against bacterial and fungal infections. Despite the beneficial roles of Th17 cells, unrestrained IL-17 production can contribute to immunopathology and inflammatory autoimmune diseases, including multiple sclerosis, rheumatoid arthritis, and inflammatory bowel disease. Although these diverse outcomes are directed by the activation of Th17 cells, the regulation of Th17 cells is incompletely understood. The discovery that microRNAs (miRNAs) are involved in the regulation of Th17 cell differentiation and function has greatly improved our understanding of Th17 cells in immune response and disease. Here, we provide an overview of the biogenesis and function of miRNA and summarize the role of miRNAs in Th17 cell differentiation and function. Finally, we focus on recent advances in miRNA-mediated dysregulation of Th17 cell fate in autoimmune diseases.

scholarly journals Redundant cytokine requirement for intestinal microbiota-induced Th17 cell differentiation in draining lymph nodes

2020 ◽  
Author(s):  
Teruyuki Sano ◽  
Takahiro Kageyama ◽  
Victoria Fang ◽  
Ranit Kedmi ◽  
Jhimmy Talbot ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Lymph Nodes ◽  
Lamina Propria ◽  
Th17 Cell ◽  
Mucosal Barrier ◽  
T Helper ◽  
Mesenteric Lymph Nodes ◽  
T Helper 17 ◽  
Th17 Cell Differentiation ◽  
Draining Lymph Nodes

SummaryDifferentiation of intestinal T helper 17 (Th17) cells, which contribute to mucosal barrier protection from invasive pathogens, is dependent on colonization with distinct commensal bacteria. Segmented filamentous bacteria (SFB) are sufficient to support Th17 cell differentiation in mouse, but the molecular and cellular requirements for this process remain incompletely characterized. Here we show that intestine-draining mesenteric lymph nodes (MLN) are the dominant site of SFB-induced intestinal Th17 cell differentiation. Subsequent migration of these cells to the intestinal lamina propria is dependent on their up-regulation of integrin β7. Stat3-dependent induction of RORγt, the Th17 cell-specifying transcription factor, largely depends on IL-6, but signaling through the receptors for IL-21 and IL-23 can compensate for absence of IL-6 to promote SFB-directed Th17 cell differentiation. These results indicate that redundant cytokine signals guide commensal microbe-dependent Th17 cell differentiation in the MLN and accumulation of the cells in the lamina propria.

scholarly journals Expression of leptin in hepatic fibrosis and its relation with hepatic stellate cell activation

2009 ◽  
Vol 17 (21) ◽  
pp. 2127
Author(s):  
Jing Xu ◽  
Jing Zhu ◽  
Liang Pan ◽  
Jing-Xian Lu ◽  
Ming-Bing Xiao ◽  
...  
Keyword(s):  
Hepatic Fibrosis ◽  
Hepatic Stellate Cell ◽  
Cell Activation ◽  
Stellate Cell ◽  
Hepatic Stellate Cell Activation
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