The Alarmin Cytokine, High Mobility Group Box 1, Is Produced by Viable Cardiomyocytes and Mediates the Lipopolysaccharide-Induced Myocardial Dysfunction via a TLR4/Phosphatidylinositol 3-Kinase γ Pathway

Xu, Hu; Su, Zhaoliang; Wu, Jun; Yang, Min; Penninger, Josef; Martin, Claudio M.; Kvietys, Peter R.; Tao, Rui

doi:10.4049/jimmunol.0902660

Cited by 86 publications

(90 citation statements)

References 40 publications

(72 reference statements)

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“…1). HMGB1 levels originated from damage to cardiac myocytes [31], fibroblasts (our unpublished data), and activation of lymphocytes.…”

Section: Discussionmentioning

confidence: 75%

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HMGB1 blockade attenuates experimental autoimmune myocarditis and suppresses Th17‐cell expansion

Sun

Zhou

et al. 2011

Eur J Immunol

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High-mobility group box 1 (HMGB1), a non-histone nuclear protein, has been implicated in cardiovascular diseases. Dilated cardiomyopathy (DCM), one of the leading causes of heart failure, is often caused by coxsackievirus B3-triggered myocarditis and promoted by the post-infectious autoimmune process. Th17 cells, a novel CD4 1 T subset, may be important in the pathogenesis of autoimmune myocarditis. In the present study, we attempted to block HMGB1 function with a monoclonal antibody specific for HMGB1 B box and investigated the effects of the blockade on Th17 cells and experimental autoimmune myocarditis (EAM). After induction of EAM, HMGB1 protein levels were significantly elevated both in the heart and blood. Administration of an anti-HMGB1 B box mAb attenuated cardiac pathological changes and reduced the number of infiltrating inflammatory cells in the heart during EAM. These protective effects of HMGB1 blockade correlated with a reduced number of Th17 cells in local tissues and lower levels of IL-17 in the serum. Furthermore, in vitro, studies demonstrated that HMGB1 promoted Th17-cell expansion. Therefore, we speculate that HMGB1 blockade ameliorates cardiac pathological changes in EAM by suppressing Th17 cells.Key words: Dilated cardiomyopathy . Experimental myocarditis . HMGB1 . Th17 cells IntroductionHigh-mobility group box 1 (HMGB1), a non-histone nuclear protein, has been functionally characterized as an alarmin or damage-associated molecular pattern (DAMP) [1,2]. It is constitutively expressed in quiescent cells and stored in the nucleus [3]. HMGB1 is one of the most evolutionarily conserved proteins in eukaryotes, with 100% identity between mice and rats, and 99% identity between rodents and humans [3].HMGB1 has been shown to be involved in both infectious and non-infectious inflammatory disease [2,4]. HMGB1 is released into the extracellular milieu during cell apoptosis/death [5], and by macrophages and monocytes in response to cellular stress or injury [6]. HMGB1 binds to the endogenous receptor for advanced glycation endproducts [7], exogenous toll-like receptor 2/4/9 (TLR2/4/9) [8,9], and CD24/Siglec-10 [10], and induces the expression of proinammatory cytokines, chemokines, and adhesion molecules [3,6]. Although, HMGB1 was initially 3586thought to be a late mediator of sepsis, recent data also indicated that HMGB1 is associated with many other pathological conditions, such as autoimmune disease [11], cancer [12][13][14], trauma, ischemia-reperfusion injury [15,16], tissue repair and regeneration [17,18], and cardiovascular diseases [19]. Furthermore, HMGB1 has restorative effects on CD4 1 T-helper cell modulation [20].Dilated cardiomyopathy (DCM) is one of the leading causes of severe heart failure and the most common indication for heart transplantation. DCM is often caused by coxsackievirus B3-triggered myocarditis [21]. Experimental autoimmune myocarditis (EAM) is a mouse model of postinfectious myocarditis, characterized by inflammatory infiltration of the myocardium and cardiac myocyte ne...

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“…1). HMGB1 levels originated from damage to cardiac myocytes [31], fibroblasts (our unpublished data), and activation of lymphocytes.…”

Section: Discussionmentioning

confidence: 75%

“…1). HMGB1 levels originated from damage to cardiac myocytes [31], fibroblasts (our unpublished data), and activation of lymphocytes.Since HMGB1 expression was increased in EAM, whether HMGB1 blockade could ameliorate cardiac pathological changes was investigated. HMGB1 blockade by mAb resulted in a Figure 3.…”

mentioning

confidence: 75%

HMGB1 blockade attenuates experimental autoimmune myocarditis and suppresses Th17‐cell expansion

Sun

Zhou

et al. 2011

Eur J Immunol

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“…20,31,33 Our data showed, for the first time, that LPS was able to induce lung fibroblasts to secrete HMGB1 and that anti-HMGB1-neutralizing antibody blocked the effects of LPS on lung fibroblast proliferation, suggesting that LPS effects on lung fibroblast proliferation are mediated, at least in large part, through HMGB1. Furthermore, these results indicate that endogenous HMGB1 can collude with LPS in stimulating lung fibroblast proliferation and thereby may function to exacerbate pulmonary fibrosis.…”

Section: Discussionmentioning

confidence: 85%

High-mobility group box 1 accelerates lipopolysaccharide-induced lung fibroblast proliferation in vitro: involvement of the NF-κB signaling pathway

Deng

et al. 2015

Laboratory Investigation

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The mechanism underlying lipopolysaccharide (LPS)-induced aberrant proliferation of lung fibroblasts in Gram-negative bacilli-associated pulmonary fibrosis is unknown. High-mobility group box 1 (HMGB1) is a ubiquitous nuclear protein that is released from the nuclei of lung fibroblasts after LPS stimulation. It can exasperate LPS-induced inflammation and hasten cell proliferation. Thus, this study investigated the effects of LPS-and/or HMGB1-stimulating murine lung fibroblasts on gene expression using various assays in vitro. Thiazolyl-diphenyl-tetrazolium bromide (MTT) assay data showed that either LPS or HMGB1 could induce lung fibroblast proliferation. Endogenous HMGB1 secreted from lung fibroblasts was detected by enzyme-linked immunosorbent assay (ELISA) 48 h after LPS stimulation. Pretreatment with an anti-HMGB1 antibody inhibited the proliferative effects of LPS on lung fibroblasts. DNA microarray data showed that the NF-κB signaling genes were upregulated in cells after stimulated with LPS, HMGB1, or both. Secretion of matrix metalloproteinase (MMP)-2 and MMP-9, and tissue inhibitor of metalloproteinase 2 (TIMP-2) was significantly upregulated after treatment with LPS, HMGB1, or their combination. However, an NF-κB inhibitor was able to downregulate levels of these proteins. In addition, levels of Toll-like receptor 4 (TLR4), Toll-like receptor 2 (TLR2), and receptors for advanced glycation end products (RAGE) mRNA and proteins were also upregulated in these cells after LPS treatment and further upregulated by LPS plus HMGB1. In conclusion, the data from the current study demonstrate that LPS-induced lung fibroblast secretion of endogenous HMGB1 can augment the proproliferative effects of LPS and, therefore, may play a key role in exacerbation of pulmonary fibrosis. The underlying molecular mechanisms are related to the activation of the TLR4/NF-κB signaling pathway and its downstream targets.

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“…38 More recently, there have been data to suggest that the high-mobility group box 1 or alarmin family of signals may also directly depress cardiac function and Ca 2+ kinetics. 39 However, this effect may be partially ameliorated through phosphatidylinositol 3 kinase-γ blockade, suggesting possible avenues for host protection.…”

Section: Cellular Mechanisms and Contractile Dysfunctionmentioning

confidence: 99%

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The Alarmin Cytokine, High Mobility Group Box 1, Is Produced by Viable Cardiomyocytes and Mediates the Lipopolysaccharide-Induced Myocardial Dysfunction via a TLR4/Phosphatidylinositol 3-Kinase γ Pathway

Cited by 86 publications

References 40 publications

HMGB1 blockade attenuates experimental autoimmune myocarditis and suppresses Th17‐cell expansion

HMGB1 blockade attenuates experimental autoimmune myocarditis and suppresses Th17‐cell expansion

High-mobility group box 1 accelerates lipopolysaccharide-induced lung fibroblast proliferation in vitro: involvement of the NF-κB signaling pathway

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