Interleukin-1alpha stimulates proinflammatory cytokine expression in human cardiac myofibroblasts.

Cardiac myofibroblasts (CMF) play a key role in infarct repair and scar formation following myocardial infarction (MI) and are also an important source of proinflammatory cytokines. We postulated that interleukin-1alpha (IL-1alpha), a potential early trigger of acute inflammation post-MI, could stimulate human CMF to express additional proinflammatory cytokines. Furthermore, we hypothesized that these effects may be modulated by the anti-inflammatory cytokine interleukin-10 (IL-10). Human CMF were cultured from atrial biopsies from multiple patients. Interleukin-1beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), and cardiotrophin-1 (CT-1) mRNA expression and secretion were measured using quantitative real-time RT-PCR and enzyme-linked immunosorbent assay. IL-1alpha (0.001-10 ng/ml, 0-6 h) stimulated IL-1beta, TNF-alpha, and IL-6 mRNA expression with distinct temporal and concentration profiles, resulting in increased cytokine secretion. The response to IL-1alpha was much greater than with TNF-alpha. Neither IL-1alpha nor TNF-alpha treatment modulated CT-1 mRNA expression. Immunoblotting with phosphospecific antibodies revealed that IL-1alpha stimulated the extracellular signal-regulated kinase (ERK)-1/2, p38 mitogen-activated protein kinase (MAPK), c-Jun NH(2)-terminal kinase (JNK), phosphatidylinositol 3-kinase (PI 3-kinase)/protein kinase B (Akt), and nuclear factor (NF)-kappaB signaling pathways. Pharmacological inhibitor studies indicated roles for PI 3-kinase/Akt and NF-kappaB pathways in mediating IL-1beta expression, and for NF-kappaB and p38 MAPK pathways in mediating TNF-alpha expression. IL-1alpha-induced IL-6 mRNA expression was reduced by p38 MAPK inhibition, but increased by ERK and JNK pathway inhibitors. IL-10 produced a consistent but modest reduction in IL-1alpha-induced IL-6 mRNA levels (not IL-1beta or TNF-alpha), but this was not reflected by reduced IL-6 protein secretion. In conclusion, IL-1alpha stimulates human CMF to express IL-1beta, TNF-alpha, and IL-6 via specific signaling pathways, responses that are unaffected by IL-10 exposure.

[1]  N. Turner,et al.  Cardiac fibroblasts: at the heart of myocardial remodeling. , 2009, Pharmacology & therapeutics.

[2]  S. Ball,et al.  PEROXISOME PROLIFERATOR‐ACTIVATED RECEPTOR γ‐INDEPENDENT EFFECTS OF THIAZOLIDINEDIONES ON HUMAN CARDIAC MYOFIBROBLAST FUNCTION , 2009, Clinical and experimental pharmacology & physiology.

[3]  N. Frangogiannis.  The immune system and cardiac repair. , 2008, Pharmacological research.

[4]  K. Chatila,et al.  Interleukin-1 receptor type I signaling critically regulates infarct healing and cardiac remodeling. , 2008, The American journal of pathology.

[5]  D. Stejskal,et al.  Cardiotrophin-1. Review. , 2008, Biomedical papers of the Medical Faculty of the University Palacky, Olomouc, Czechoslovakia.

[6]  G. Biondi-Zoccai,et al.  Anakinra, a Recombinant Human Interleukin-1 Receptor Antagonist, Inhibits Apoptosis in Experimental Acute Myocardial Infarction , 2008, Circulation.

[7]  M. Capogrossi,et al.  HMGB1-stimulated human primary cardiac fibroblasts exert a paracrine action on human and murine cardiac stem cells. , 2008, Journal of molecular and cellular cardiology.

[8]  Rodney W. Johnson,et al.  Effects of IL-10 and age on IL-6, IL-1beta, and TNF-alpha responses in mouse skeletal and cardiac muscle to an acute inflammatory insult. , 2008, Journal of applied physiology.

[9]  M. Goumans,et al.  Toll-Like Receptor 4 Mediates Maladaptive Left Ventricular Remodeling and Impairs Cardiac Function After Myocardial Infarction , 2008, Circulation research.

[10]  P. Cohen,et al.  The selectivity of protein kinase inhibitors: a further update. , 2007, The Biochemical journal.

[11]  S. Ball,et al.  Mechanism of TNFα-induced IL-1α, IL-1β and IL-6 expression in human cardiac fibroblasts : Effects of statins and thiazolidinediones , 2007 .

[12]  S. Akira,et al.  Identification of a key pathway required for the sterile inflammatory response triggered by dying cells , 2007, Nature Medicine.

[13]  M. Becich,et al.  Cardiac fibroblasts influence cardiomyocyte phenotype in vitro. , 2007, American journal of physiology. Cell physiology.

[14]  M. Entman,et al.  Interleukin-10 is not a critical regulator of infarct healing and left ventricular remodeling. , 2007, Cardiovascular research.

[15]  K. Werdan,et al.  Endotoxin-activated cultured neonatal rat cardiomyocytes express functional surface-associated interleukin-1α , 2007, Journal of endotoxin research.

[16]  C. Long,et al.  IL-1beta stimulates rat cardiac fibroblast migration via MAP kinase pathways. , 2007, American journal of physiology. Heart and circulatory physiology.

[17]  P. Murray.  Understanding and exploiting the endogenous interleukin-10/STAT3-mediated anti-inflammatory response. , 2006, Current opinion in pharmacology.

[18]  F. Ohsuzu,et al.  Left ventricular hypertrophy in mice with a cardiac-specific overexpression of interleukin-1. , 2006, American journal of physiology. Heart and circulatory physiology.

[19]  Chun Xing Li,et al.  Noncanonical cAMP pathway and p38 MAPK mediate beta2-adrenergic receptor-induced IL-6 production in neonatal mouse cardiac fibroblasts. , 2006, Journal of molecular and cellular cardiology.

[20]  B. Greenberg,et al.  IL-1β and TNF-α upregulate angiotensin II type 1 (AT1) receptors on cardiac fibroblasts and are associated with increased AT1 density in the post-MI heart , 2005 .

[21]  S. Ball,et al.  Simvastatin reduces human atrial myofibroblast proliferation independently of cholesterol lowering via inhibition of RhoA. , 2004, Cardiovascular research.

[22]  B. Jugdutt,et al.  Ventricular remodeling after infarction and the extracellular collagen matrix: when is enough enough? , 2003, Circulation.

[23]  S. Ball,et al.  Chronic beta2-adrenergic receptor stimulation increases proliferation of human cardiac fibroblasts via an autocrine mechanism. , 2003, Cardiovascular research.

[24]  Peter J. Murray,et al.  Shaping Gene Expression in Activated and Resting Primary Macrophages by IL-101 , 2002, The Journal of Immunology.

[25]  H. Gascan,et al.  Secretion of IL-6, IL-11 and LIF by human cardiomyocytes in primary culture. , 2002, Cytokine.

[26]  F. Ohsuzu,et al.  Myocardial hypertrophy in transgenic mice overexpressing human interleukin 1alpha. , 2001, Journal of cardiac failure.

[27]  M. Suematsu,et al.  ERK and p38 MAPK, but not NF-&kgr;B, Are Critically Involved in Reactive Oxygen Species–Mediated Induction of IL-6 by Angiotensin II in Cardiac Fibroblasts , 2001, Circulation research.

[28]  Y. Kaneda,et al.  Overexpression of Interleukin-1 Receptor Antagonist Provides Cardioprotection Against Ischemia-Reperfusion Injury Associated With Reduction in Apoptosis , 2001, Circulation.

[29]  D. Lefer,et al.  Cardioprotective actions of endogenous IL-10 are independent of iNOS. , 2001, American journal of physiology. Heart and circulatory physiology.

[30]  A. Deten,et al.  Catecholamines stimulate interleukin-6 synthesis in rat cardiac fibroblasts. , 2001, American journal of physiology. Heart and circulatory physiology.

[31]  S. Ball,et al.  The mechanism of angiotensin II-induced extracellular signal-regulated kinase-1/2 activation is independent of angiotensin AT(1A) receptor internalisation. , 2001, Cellular signalling.

[32]  W. V. Berghe,et al.  Signal transduction by tumor necrosis factor and gene regulation of the inflammatory cytokine interleukin-6. , 2000, Biochemical pharmacology.

[33]  S. Makino,et al.  Interleukin-6 Family of Cytokines Mediate Angiotensin II-induced Cardiac Hypertrophy in Rodent Cardiomyocytes* , 2000, The Journal of Biological Chemistry.

[34]  A. Dunne,et al.  The Interleukin-1 Receptor/Toll-Like Receptor Superfamily: Signal Transduction During Inflammation and Host Defense , 2000, Science's STKE.

[35]  W. Colucci,et al.  Interleukin-1β and Tumor Necrosis Factor-α Decrease Collagen Synthesis and Increase Matrix Metalloproteinase Activity in Cardiac Fibroblasts In Vitro , 2000 .

[36]  K. Weber,et al.  Infarct scar: a dynamic tissue. , 2000, Cardiovascular research.

[37]  Z. Yang,et al.  Crucial role of endogenous interleukin-10 production in myocardial ischemia/reperfusion injury. , 2000, Circulation.

[38]  M. Spence,et al.  Cloning and characterization of human oncostatin M promoter. , 1999, Nucleic acids research.

[39]  I. Masuda,et al.  Involvement of cardiotrophin-1 in cardiac myocyte-nonmyocyte interactions during hypertrophy of rat cardiac myocytes in vitro. , 1999, Circulation.

[40]  E. Fleck,et al.  Cloning and characterization of the 5'-flanking region of the human cardiotrophin-1 gene. , 1998, Biochemical and biophysical research communications.

[41]  C. Dinarello,et al.  Biologic basis for interleukin-1 in disease. , 1996, Blood.

[42]  A. C. Webb,et al.  Interleukin-1: a gene expression system regulated at multiple levels. , 1994, European cytokine network.

[43]  C. Jongeneel,et al.  Enhancers and transcription factors controlling the inducibility of the tumor necrosis factor-alpha promoter in primary macrophages. , 1991, Journal of immunology.

[44]  E. Braunwald,et al.  Myocardial reperfusion: a double-edged sword? , 1985, The Journal of clinical investigation.

[45]  M. Jeyaraman,et al.  High- but not low-molecular weight FGF-2 causes cardiac hypertrophy in vivo; possible involvement of cardiotrophin-1. , 2007, Journal of molecular and cellular cardiology.

[46]  M. Nishida,et al.  Heterotrimeric G protein G alpha13-induced induction of cytokine mRNAs through two distinct pathways in cardiac fibroblasts. , 2006, Journal of pharmacological sciences.

[47]  C. Long,et al.  The cardiac fibroblast: therapeutic target in myocardial remodeling and failure. , 2005, Annual review of pharmacology and toxicology.

[48]  T. Borg,et al.  Structural and functional characterisation of cardiac fibroblasts. , 2005, Cardiovascular research.

[49]  K. Weber.  Fibrosis in hypertensive heart disease: focus on cardiac fibroblasts. , 2004, Journal of hypertension.

[50]  M. Entman,et al.  The inflammatory response in myocardial infarction. , 2002, Cardiovascular research.