Extracellular heat shock protein 90 induces interleukin-8 in vascular smooth muscle cells

Chung, Sungwook; Lee, Ji Hyuk; Choi, Kyung-Ha; Park, Young-Chul; Eo, Seong-Kug; Rhim, Byung Yong; Kim, Koanhoi

doi:10.1016/j.bbrc.2008.11.063

Cited by 26 publications

(16 citation statements)

References 25 publications

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“…McCready et al reported that eHsp90α exogenously delivered by added exosomes participated in plasminogen activation and tumor cell migration [57]. Moreover, Chung et al showed that eHsp90 secreted by stressed vascular SMCs regulates transcription of IL-8 gene [58]. While it is still distant from understanding the mechanisms of action, these results at the least suggest that eHsp90 has multiple downstream targets in distinct extracellular environment.…”

Section: Downstream Targets Of Ehsp90mentioning

confidence: 99%

Secreted heat shock protein-90 (Hsp90) in wound healing and cancer

Sahu

Tsen

2012

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

166

181

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Summary Extracellular Hsp90 proteins, including “membrane-bound”, “released” and “secreted”, were first reported more than two decades ago. Only studies of the past seven years have begun to reveal a picture for when, how and why Hsp90 get exported by both normal and tumor cells. Normal cells secrete Hsp90 in response to tissue injury. Tumor cells have managed to constitutively secrete Hsp90 for tissue invasion. In either case, sufficient supply of the extracellular Hsp90 can be guaranteed by its unusually abundant storage inside the cells. A well-characterized function of secreted Hsp90α is to promote cell motility, a crucial event for both wound healing and cancer. The reported targets for extracellular Hsp90α include MMP2, LRP-1, tyrosine kinase receptors and possibly more. The pro-motility activity of secreted Hsp90α resides within a fragment at the boundary between linker region and middle domain. Inhibition of its secretion, neutralization of its extracellular action or interruption of its signaling through LRP-1 block wound healing and tumor invasion in vitro and in vivo. In normal tissue, topical application of F-5 promotes acute and diabetic wound healing far more effectively than US FDA-approved conventional growth factor therapy in mice. In cancer, drugs that selectively target the F-5 region of secreted Hsp90 by cancer cells may be more effective and less toxic than those that target the ATPase of the intracellular Hsp90.

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Section: Downstream Targets Of Ehsp90mentioning

confidence: 99%

Secreted heat shock protein-90 (Hsp90) in wound healing and cancer

Sahu

Tsen

2012

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

166

181

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“…Extracellular Hsp90-mediated modulation of proinflammatory cytokines has been reported earlier (54). The autocrine effect of TNFR-1 in myocyte-derived exosomes during hypoxia and the paracrine effect on myocytes by IL-6-containing exosomes from macrophages during sepsis were shown previously (55,56).…”

Section: Fig 11mentioning

confidence: 69%

Myocyte-Derived Hsp90 Modulates Collagen Upregulation via Biphasic Activation of STAT-3 in Fibroblasts during Cardiac Hypertrophy

Datta

Bansal

Rana

et al. 2017

Molecular and Cellular Biology

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Signal transducer and activator of transcription 3 (STAT-3)-mediated signaling in relation to upregulated collagen expression in fibroblasts during cardiac hypertrophy is well defined. Our recent findings have identified heat shock protein 90 (Hsp90) to be a critical modulator of fibrotic signaling in cardiac fibroblasts in this disease milieu. The present study was therefore intended to analyze the role of Hsp90 in the STAT-3-mediated collagen upregulation process. Our data revealed a significant difference between in vivo and in vitro results, pointing to a possible involvement of myocyte-fibroblast cross talk in this process. Cardiomyocyte-targeted knockdown of Hsp90 in rats (Rattus norvegicus) in which the renal artery was ligated showed downregulated collagen synthesis. Furthermore, the results obtained with cardiac fibroblasts conditioned with Hsp90-inhibited hypertrophied myocyte supernatant pointed toward cardiomyocytes' role in the regulation of collagen expression in fibroblasts during hypertrophy. Our study also revealed a novel signaling mechanism where myocyte-derived Hsp90 orchestrates not only p65-mediated interleukin-6 (IL-6) synthesis but also its release in exosomal vesicles. Such myocyte-derived exosomes and myocyte-secreted IL-6 are responsible in unison for the biphasic activation of STAT-3 signaling in cardiac fibroblasts that culminates in excess collagen synthesis, leading to severely compromised cardiac function during cardiac hypertrophy.KEYWORDS cardiac hypertrophy, collagen, Hsp90, myocyte-fibroblast cross talk, STAT-3 M yocardial fibrosis is a hallmark of cardiac hypertrophy and a proposed substrate for heart failure (1, 2). The extracellular space is frequently the site for such abnormal accumulation of fibrillar collagen, accounting for myocardial stiffness and ventricular dysfunction during cardiac hypertrophy (3). The cardiac fibroblast is the principal cell type in the myocardium and synthesizes and secretes collagen in response to pressure-overload hypertrophy (4). A close relationship between angiotensin II (AngII) and profibrotic cytokines has been suggested, and several molecular signaling networks have been implicated in the progression of cardiac fibrosis (5, 6). A few reports have also shown that the role of myocytes in myocardial collagen production is mediated by myocyte-derived paracrine factors (7,8). However, the precise mechanisms involving the role of different signaling intermediates in the regulation of collagen gene expression during cardiac hypertrophy have remained unsolved.In an earlier report, we described the mechanism of interleukin-6 (IL-6)-mediated activation of the signal transducer and activator of transcription 3 (STAT-3) and consequent collagen synthesis in the hypertrophied rat heart (9). STAT-3 activation has also

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“…Additionally, for the intestinal contractile cells some parallels might be drawn from investigations on vascular smooth muscle cells. It has been shown that ligation of TLR4 by either LPS or extracellular heat shock protein 90 converted cultured human aortic muscle cells into a proinflammatory phenotype in a MyD88-dependent fashion (12,29). On the other hand, although in vivo E. coli-induced vascular dysfunction was TLR4 dependent, the functional change showed only an incomplete necessity of both MyD88 and TRIF signaling (10).…”

Section: Discussionmentioning

confidence: 96%

Dominant role of the MyD88-dependent signaling pathway in mediating early endotoxin-induced murine ileus

Buchholz

Billiar

Bauer

2010

American Journal of Physiology-Gastrointestinal and Liver Physi

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TLR4 ligation by pathogen-associated molecular patterns, such as Gram-negative bacteria-derived LPS, triggers a nonhematopoietic cell-mediated ileus during early endotoxemia. Our objective was to investigate the quantitative contributions of the two downstream signaling pathways of TLR4, namely the adapter proteins myeloid differentiation primary response gene 88 (MyD88) and Toll-IL-1-resistance (TIR) domain-containing adaptor-inducing IFN-beta (TRIF). Six hours after intraperitoneal injection of highly purified LPS (UP-LPS, 5 mg/kg), in vivo gastrointestinal transit and intestinal muscularis gene transcripts of inflammatory mediators chemokine (C-X-C motif) ligand 10, synonymous IP-10 (CXCL10), granulomonocyte colony stimulating factor (GM-CSF, synonymous CSF-2), IL-1beta, IL-6, IL-10, and inducible NO synthase (iNOS) were assessed in mice with transgenic loss-of-function for MyD88 or TRIF. LPS-induced MyD88 and TRIF mRNA upregulation was quantified within the intestinal muscularis of TLR4-competent and TLR4-mutant mice, and MyD88 mRNA levels were additionally measured in TLR4 bone marrow chimeras. MyD88 deficiency completely protected mice from early endotoxin-induced ileus, while TRIF deficiency partially ameliorated ileus severity. LPS induction of the primary downstream signaling element MyD88 was TLR4 dependent and was derived in equal amounts from both the hematopoietic and the nonhematopoietic cells. Conversely, no induction of TRIF mRNA was detectable. Significant gene induction of all inflammatory mediators was dependent on intracellular signal transduction by MyD88, while the TRIF MyD88-independent pathway predominantly regulated the molecular levels of CXCL10. In summary, MyD88 and TRIF are nonredundant signaling pathways in early endotoxin-induced rodent ileus, but MyD88 is the essential adaptor molecule for transduction of early TLR4-induced ileus and inflammatory signaling. The dependency of ileus on individual adaptor protein pathways is also reflected in the manifestation of specific molecular inflammatory events within the intestinal muscularis externa.

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Extracellular heat shock protein 90 induces interleukin-8 in vascular smooth muscle cells

Cited by 26 publications

References 25 publications

Secreted heat shock protein-90 (Hsp90) in wound healing and cancer

Secreted heat shock protein-90 (Hsp90) in wound healing and cancer

Myocyte-Derived Hsp90 Modulates Collagen Upregulation via Biphasic Activation of STAT-3 in Fibroblasts during Cardiac Hypertrophy

Dominant role of the MyD88-dependent signaling pathway in mediating early endotoxin-induced murine ileus

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