Leukemia Inhibitory Factor, a Potent Cardiac Hypertrophic Cytokine, Activates the JAK/STAT Pathway in Rat Cardiomyocytes

Kodama, Hiroaki; Fukuda, Keiichi; Pan, Jing; Makino, Shinji; Baba, Akira; Hori, Shingo; Ogawa, Satoshi

doi:10.1161/01.res.81.5.656

Cited by 148 publications

(103 citation statements)

References 55 publications

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“…Moreover, activation of the gp130 receptor has been reported to induce cardiac myocyte hypertrophy both in vivo and in vitro (10,37). Further reports have shown that the JAK-STAT pathway, especially the STAT3-mediated pathway, appears to be essential in the induction of cardiac myocyte hypertrophy through gp130 (13,14). This study is the first to demonstrate that CT-1, which acts through a gp130/leukemia inhibitory factor receptor heterodimer, has the ability to induce ASM hypertrophy in the tissue milieu and that the hypertrophy is associated with increased deposition of extracellular matrix, findings consistent with our studies in severe asthma (3).…”

Section: Discussionmentioning

confidence: 99%

Cardiotrophin-1 alters airway smooth muscle structure and mechanical properties in airway explants

Zheng

Zhou

Seow

et al. 2004

American Journal of Physiology-Lung Cellular and Molecular Phys

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Cardiotrophin-1 alters airway smooth muscle structure and mechanical properties in airway explants. Am J Physiol Lung Cell Mol Physiol 287: L1165-L1171, 2004. First published July 23, 2004 doi:10.1152/ ajplung.00171.2004.-Induction of hypertrophy and inhibition of apoptosis may be important mechanisms contributing to increased airway smooth muscle (ASM) mass in asthma. Data from our laboratory indicate that cardiotrophin-1 (CT-1) induces hypertrophy and inhibits apoptosis in isolated human ASM cells. To determine whether these novel effects of CT-1 also occur in the airway tissue milieu and to determine whether structural changes are accompanied by functional changes, matched pairs of guinea pig airway explants were treated with or without CT-1 for 7 days, and structural features as well as isometric and isotonic contractile and relaxant mechanical properties were measured. CT-1 (0.2-5 ng/ml) increased both myocyte mass and extracellular matrix in a concentration-dependent fashion. CT-1 (10 ng/ml)-treated tissues exhibited a significant increase in passive tension at all lengths on day 7; at optimal length, passive tension generated by CT-1-treated tissues was 1.72 Ϯ 0.12 vs. 1.0 Ϯ 0.1 g for control. Maximal isometric stress was decreased in the CT-1-treated group on day 7 (0.39 Ϯ 0.10 kg/cm 2 ) vs. control (0.77 Ϯ 0.15 kg/cm 2 , P Ͻ 0.05). Isoproterenol-induced relaxant potency was reduced in CT-1-treated tissues, log EC50 being Ϫ7.28 Ϯ 0.34 vs. Ϫ8.12 Ϯ 0.25 M in control, P Ͻ 0.05. These data indicate that CT-1 alters ASM structural and mechanical properties in the tissue environment and suggest that structural changes found in the airway wall in asthma are not necessarily associated with increased responsiveness. tracheal explants; mechanics; cytokines; asthma; matrix; smooth muscle hypertrophy INCREASED SMOOTH MUSCLE MASS has been repeatedly documented in asthmatic subjects (3,11,29,33,34), but the mechanisms responsible for the increased mass are unclear. The amount of both airway smooth muscle (ASM) and smooth muscle-associated matrix is greater with increased duration of asthma and may be an important determinant of the severity of airway responsiveness (3,15). Yet the functional alterations in ASM in asthma are uncertain (29, 34). When bronchial segments from asthmatics have been studied in vitro, the majority of studies have shown no change in mechanical properties, although isolated cells from asthmatics show a higher velocity of shortening (16). Tracheal tissue offers some advantages in studies of ASM behavior in that the muscle is more uniform in orientation, and less matrix elements are present. The only study of asthmatic trachea, in severe asthma, showed a nonspecific increase in force generation, suggesting increased contractility. However, force was normalized to tissue weight, not muscle mass (1); thus, the changes could have been a reflection of increased muscle.Cardiotrophin-1 (CT-1), a member of the IL-6 family, was initially defined as a factor that has the capacity to induce cardiac myocyt...

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Section: Discussionmentioning

confidence: 99%

Cardiotrophin-1 alters airway smooth muscle structure and mechanical properties in airway explants

Zheng

Zhou

Seow

et al. 2004

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…12 Notably, in addition to STAT3 dimers, STAT1 and STAT3 heterodimers also exist and may possess transcriptional potential that differs from the potential of STAT1 or STAT3. 9,22,23 Additionally, the DNA-binding fold contains several b-sheets that are folded similarly to the sheets found in the DNA-binding domains of NFKB1 and TP53, which suggests that numerous crosstalk possibilities exist among these 3 important stress responsive pathways. For example, NFKB1 is activated through endoplasmic reticulum stress signals in starved cancer cells, resulting in the induction of IL6.…”

Section: The Structure and Subcellular Localization Of Stat3mentioning

confidence: 99%

The role of STAT3 in autophagy

et al. 2015

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Abbreviations: ALK, anaplastic lymphoma receptor tyrosine kinase; ATF4, activating transcription factor 4; BNIP3, BCL2/adenovirus E1B 19kDa interacting protein 3; CNTF, ciliary neurotrophic factor; COX8, cytochrome c oxidase subunit VIII; ConA, concanavalin A; CTSB, cathepsin B; CTSL, cathepsin L; CuB, cucurbitacin B; CYCS, cytochrome c, somatic; EGF, epidermal growth factor; EIF2A, eukaryotic initiation factor 2A, 65kDa; EIF2AK2, eukaryotic translation initiation factor 2-a kinase 2; ER, endoplasmic reticulum; ETC, electron transport chain; FOXO1/3, forkhead box O1/3; HDAC3, histone deacetylase 3; HIF1A, hypoxia inducible factor 1, a subunit (basic helix-loop-helix transcription factor); IL6, interleukin 6; IMM, inner mitochondrial membrane; KDR, kinase insert domain receptor; LMP, lysosomal membrane permeabilization; MAPK1, mitogen-activated protein kinase 1; MAP1LC3A, microtubule-associated protein 1 light chain 3 a; miRNA, microRNA; mitoSTAT3, mitochondrial STAT3; MLS, mitochondrial localization sequence; MMP14, matrix metallopeptidase 14 (membrane-inserted); NDUFA13, NADH dehydrogenase (ubiquinone) 1 a subcomplex, 13; NES, nuclear export signal; NFKB1, nuclear factor of kappa light polypeptide gene enhancer in B-cells 1; NLS, nuclear localization signal; PDGFRB, platelet-derived growth factor receptor, b polypeptide; PRKAA2, protein kinase, AMP-activated, a 2 catalytic subunit; PTPN2, protein tyrosine phosphatase, non-receptor type 2; PTPN6, protein tyrosine phosphatase, non-receptor type 6; PTPN11, protein tyrosine phosphatase, non-receptor type 11; ROS, reactive oxygen species; RTK, receptor tyrosine kinases; SH2, src homology 2; STAT3, signal transducer and activator of transcription 3 (acute-phase response factor); VHL, von Hippel-Lindau tumor suppressor, E3 ubiquitin protein ligase; XPO1, exportin 1.Autophagy is an evolutionarily conserved process in eukaryotes that eliminates harmful components and maintains cellular homeostasis in response to a series of extracellular insults. However, these insults may trigger the downstream signaling of another prominent stress responsive pathway, the STAT3 signaling pathway, which has been implicated in multiple aspects of the autophagic process. Recent reports further indicate that different subcellular localization patterns of STAT3 affect autophagy in various ways. For example, nuclear STAT3 fine-tunes autophagy via the transcriptional regulation of several autophagy-related genes such as BCL2 family members, BECN1, PIK3C3, CTSB, CTSL, PIK3R1, HIF1A, BNIP3, and microRNAs with targets of autophagy modulators. Cytoplasmic STAT3 constitutively inhibits autophagy by sequestering EIF2AK2 as well as by interacting with other autophagy-related signaling molecules such as FOXO1 and FOXO3. Additionally, the mitochondrial translocation of STAT3 suppresses autophagy induced by oxidative stress and may effectively preserve mitochondria from being degraded by mitophagy. Understanding the role of STAT3 signaling in the regulation of autophagy may provide insight into the cla...

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“…LIF stimulation increases cardiomyocyte growth and promotes a fetal gene expression pattern (upregulated c-fos, β-MHC and ANF) [77,92]. Characteristically, LIF induces myocardial hypertrophy with a predominant increase in myocardial cell length by addition of new sarcomeric units in series without concomitant increase in cell width, clearly distinguishing it from alpha-adrenergic hypertrophic responses mediated by G protein coupled receptors [75,163].…”

Section: Leukemia Inhibitory Factor and Its Potential Role In The Heartmentioning

confidence: 99%

Survival pathways in hypertrophy and heart failure: The gp130-STAT3 axis

2007

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■ Abstract Circulating levels of interleukin (IL)-6 and related cytokines are elevated in patients with congestive heart failure and after myocardial infarction. Serum IL-6 concentrations are related to decreasing functional status of these patients and provide important prognostic information. Moreover, in the failing human heart, multiple components of the IL-6-glycoprotein (gp)130 receptor system are impaired, implicating an important role of this system in cardiac pathophysiology.Experimental studies have shown that the common receptor subunit of IL-6 cytokines is phosphorylated in response to pressure overload and myocardial infarction and that it subsequently activates at least three different downstream signaling pathways, the signal transducers and activators of transcription 1 and 3 (STAT1/3), the Src-homology tyrosine phosphatase 2 (SHP2)-Ras-ERK, and the PI3K-Akt system. Gp130 receptor mediated signaling promotes cardiomyocyte survival, induces hypertrophy, modulates cardiac extracellular matrix and cardiac function. In this regard, the gp130 receptor system and its main downstream mediator STAT3 play a key role in cardioprotection.This review summarizes the current knowledge of IL-6 cytokines, gp130 receptor and STAT3 signaling in the heart exposed to physiological (aging, pregnancy) and pathophysiological stress (ischemia, pressure overload, inflammation and cardiotoxic agents) with a special focus on the potential role of individual IL-6 cytokines.

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Leukemia Inhibitory Factor, a Potent Cardiac Hypertrophic Cytokine, Activates the JAK/STAT Pathway in Rat Cardiomyocytes

Cited by 148 publications

References 55 publications

Cardiotrophin-1 alters airway smooth muscle structure and mechanical properties in airway explants

Cardiotrophin-1 alters airway smooth muscle structure and mechanical properties in airway explants

The role of STAT3 in autophagy

Survival pathways in hypertrophy and heart failure: The gp130-STAT3 axis

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