Interleukin-6 derived from hypoxic myocytes promotes neutrophil-mediated reperfusion injury in myocardium

Sawa, Yoshiki; Ichikawa, Hajime; Kagisaki, Koji; Ohata, Toshihiro; Matsuda, Hikaru

doi:10.1016/s0022-5223(98)70018-2

Cited by 111 publications

(82 citation statements)

References 16 publications

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“…IL6 secretion has been demonstrated to be facilitated by hypoxia in human umbilical vein and pulmonary endothelial cells, primary human pulmonary fibroblasts and vascular smooth muscle cells, and Kupffer cells as well as whole pulmonary artery organoid cultures (Yan et al, 1995(Yan et al, , 1997Tamm et al, 1998;Ziesche et al, 1996;Kotake-Nara et al, 2005;Sawa et al, 1998;Hartmann et al, 2000). Our previous studies found that the level of IL-6 was increased in pulmonary tissues of rats with hypoxia-induced pulmonary hypertension .…”

Section: Discussionmentioning

confidence: 94%

“…A number of studies have demonstrated that secretion of interleukins is facilitated by hypoxia (Yan et al, 1995(Yan et al, , 1997Tamm et al, 1998;Ziesche et al, 1996;Kotake-Nara et al, 2005;Sawa et al, 1998;Hartmann et al, 2000). Several studies have also indicated that Janus kinases (JAKs) and signal transducers and activators of transcription (STATs) are activated by interleukin 6 (IL6) in cardiomyocytes, macrophages, carcinoma cells and neurons and by hypoxia in pulmonary arterial smooth muscle cells, rat cardiomyocytes, retinal microvascular endothelial cells (Negoro et al, 2001;Mascareno et al, 2005;Wang et al, 2005;Dawn et al, 2004;Lee et al, 2006;Yamauchi et al, 2006;Terrell et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

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Sequential activation of JAKs, STATs and xanthine dehydrogenase/oxidase by hypoxia in lung microvascular endothelial cells

Wang

Pei

Jackson

et al. 2008

The International Journal of Biochemistry & Cell Biology

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Xanthine dehydrogenase/oxidase (XDH/XO) is associated with various pathological conditions related to the endothelial injury. However, the molecular mechanism underlying the activation of XDH/XO by hypoxia remains largely unknown. In this report, we determined whether the Janus kinases (JAKs) and signal transducers and activators of transcription (STATs) signaling pathway is involved in hypoxia-induced activation of XDH/XO in primary cultures of lung microvascular endothelial cells (LMVEC). We found that hypoxia significantly increased interleukin 6 (IL6) production in a time-dependent manner in LMVEC. Hypoxia also markedly augmented phosphorylation/activation of JAKs (JAK1, JAK2 and JAK3) and the JAK downstream effectors STATs (STAT3 and STAT5). Hypoxia-induced activation of STAT3 was blocked by IL6 antibodies, the JAK inhibitor AG490 and the suppressor of cytokine signaling 3 (SOCS3), implying that hypoxiapromoted IL6 secretion activates the JAK/STAT pathway in LMVEC. Phosphorylation and DNAbinding activity of STAT3 was also inhibited by the p38 MAPK inhibitor SB203580 and the phosphatidylinositol 3-kinase inhibitor LY294002, suggesting that multiple signaling pathways involved in STAT activation by hypoxia. Importantly, hypoxia promoted XDH/XO activation in LMVEC, which was markedly reversed by inhibiting the JAK/STAT pathway using IL6 antibodies, AG490 and SOCS3. These data demonstrated that JAKs, STATs and XDH/XO were sequentially activated by hypoxia. These data also provide the first evidence indicating that the JAK-STAT pathway is involved in hypoxia-mediated XDH/XO activation in LMVEC.

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Section: Discussionmentioning

confidence: 94%

Section: Introductionmentioning

confidence: 99%

Sequential activation of JAKs, STATs and xanthine dehydrogenase/oxidase by hypoxia in lung microvascular endothelial cells

Wang

Pei

Jackson

et al. 2008

The International Journal of Biochemistry & Cell Biology

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“…After binding to its receptor, IL-6 elicits numerous effects including antibody induction, hematopoiesis, thrombocytopoiesis, and acute-phase protein synthesis (1,2). Significant increases in serum levels of IL-6 and its mRNA and protein expression in cardiac tissues have been reported in patients with several cardiac diseases including congestive heart failure (3-5), myocarditis (3), septic cardiomyopathy (6), myocardial infarction (7)(8)(9), cardiac myxoma (10), and the cell injury associated with ischemia/reperfusion (11) and cardiopulmonary bypass (12). Thus, IL-6 has been suggested to play an important role in the pathophysiology of these cardiac disorders.…”

Section: Il-6mentioning

confidence: 99%

JAK2/STAT3, Not ERK1/2, Mediates Interleukin-6-induced Activation of Inducible Nitric-oxide Synthase and Decrease in Contractility of Adult Ventricular Myocytes

Kennedy

Liu

2003

Journal of Biological Chemistry

135

119

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Interleukin (IL)-6 decreases cardiac contractility via a nitric oxide (NO)-dependent pathway. However, mechanisms underlying IL-6-induced NO production remain unclear. JAK2/STAT3 and ERK1/2 are two well known signaling pathways activated by IL-6 in non-cardiac cells. However, these IL-6-activated pathways have not been identified in adult cardiac myocytes. In this study, we identified activation of these two pathways during IL-6 stimulation and examined their roles in IL-6-induced NO production and decrease in contractility of adult ventricular myocytes. IL-6 increased phosphorylation of STAT3 (at Tyr 705 ) and ERK1/2 (at Tyr 204 ) within 5 min that peaked at 15-30 min and returned to basal levels at 2 h. Phosphorylation of STAT3 was blocked by genistein, a protein tyrosine kinase inhibitor, and AG490, a JAK2 inhibitor, but not PD98059, an ERK1/2 kinase inhibitor. The phosphorylation of ERK1/2 was blocked by PD98059 and genistein but not AG490. Furthermore, IL-6 enhanced de novo synthesis of iNOS protein, increased NO production, and decreased cardiac contractility after 2 h of incubation. These effects were blocked by genistein and AG490 but not PD98059. We conclude that IL-6 activated independently the JAK2/STAT3 and ERK1/2 pathways, but only JAK2/ STAT3 signaling mediated the NO-associated decrease in contractility.

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“…[57][58][59][60] In the myocardial ischemia-reperfusion model, Kukielka et al 59 showed that IL-6 played an important role in the induction of ICAM-1 in the ischemic regions. Regarding the clinical study also, Ohtsuka et al 61 clearly showed that serum levels of (c) and (d) Specimens from the border region between nonischemic and ischemic myocardium exposed to 30 min of ischemia followed by 3 h of reperfusion.…”

Section: Discussionmentioning

confidence: 99%

Interleukin-6/soluble interleukin-6 receptor complex reduces infarct size via inhibiting myocardial apoptosis

Matsushita

Iwanaga

Oda

et al. 2005

Laboratory Investigation

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Apoptosis of cardiomyocytes plays an important role in reperfusion injury following myocardial infarction. Conversely, interleukin-6 (IL-6)-a potent cytokine-inhibits myeloma cell apoptosis by activating GP130 through the IL-6 receptor (IL-6R). We hypothesized that the IL-6/soluble IL-6R complex can inhibit myocardial apoptosis, and limit infarct size in reperfused acute myocardial infarction. Anesthetized rats were randomly divided into five groups: sham, coronary occlusion and reperfusion rats administered IL-6/soluble IL-6R complex, IL-6 alone, soluble IL-6R (sIL-6R) alone, or a control vehicle. Rats were subjected to 30 min occlusion of the left coronary artery followed by 3 h reperfusion. After reperfusion, the hearts were excised. For detection and quantification of apoptosis, gel electrophoresis of extracted genomic DNA and TUNEL method of paraffin sections were performed. The percentage of the infarct area was measured using tetrazolium chloride staining. The cardiomyocyte apoptosis analysis revealed that apoptosis in the reperfused myocardium was inhibited only in the complex group. Furthermore, the percentage of the infarct area out of the area at risk was remarkably reduced in the complex group (23.871.8%), compared with that in the vehicle (37.973.7%), the IL-6 (40.771.0%), or the sIL-6R (37.572.4%) groups (P ¼ 0.0002). No significant differences were observed among the vehicle, IL-6, and sIL-6R groups. The IL-6/soluble IL-6 receptor complex inhibits cardiomyocyte apoptosis in reperfused acute myocardial infarction. It possibly reduces irreversible reperfusion injury.

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Interleukin-6 derived from hypoxic myocytes promotes neutrophil-mediated reperfusion injury in myocardium

Abstract: Interleukin-6 is produced from myocardium during ischemia and reperfusion in patients undergoing coronary bypass grafting. This interleukin-6 may be derived from hypoxic myocytes and play a role in neutrophil-mediated reperfusion injury in myocardium.

Cited by 111 publications

References 16 publications

Sequential activation of JAKs, STATs and xanthine dehydrogenase/oxidase by hypoxia in lung microvascular endothelial cells

Sequential activation of JAKs, STATs and xanthine dehydrogenase/oxidase by hypoxia in lung microvascular endothelial cells

JAK2/STAT3, Not ERK1/2, Mediates Interleukin-6-induced Activation of Inducible Nitric-oxide Synthase and Decrease in Contractility of Adult Ventricular Myocytes

Interleukin-6/soluble interleukin-6 receptor complex reduces infarct size via inhibiting myocardial apoptosis

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