Modulation of interleukin signalling and gene expression in cardiac myocytes by endothelin-1.
The related inflammatory cytokines, interleukin- (IL-) 1beta and IL-33, are both implicated in the response of the heart to injury. They also activate mitogen-activated protein kinases (MAPKs) in cardiac myocytes. The hypertrophic Gq protein-coupled receptor agonist endothelin-1 is a potentially cardioprotective peptide and may modulate the inflammatory response. Endothelin-1 also stimulates (MAPKs) in cardiac myocytes and promotes rapid changes in expression of mRNAs encoding intercellular and intracellular signalling components including receptors for IL-33 (ST2) and phosphoprotein phosphatases. Prior exposure to endothelin-1 may specifically modulate the response to IL-33 and, more globally, influence MAPK activation by different stimuli. Neonatal rat ventricular myocytes were exposed to IL-1beta or IL-33 with or without pre-exposure to endothelin-1 (5h) and MAPK activation assessed. IL-33 activated ERK1/2, JNKs and p38-MAPK, but to a lesser degree than IL-1beta. Endothelin-1 increased expression of soluble IL-33 receptors (sST2 receptors) which may prevent binding of IL-33 to the cell-surface receptors. However, pretreatment with endothelin-1 only inhibited activation of p38-MAPK by IL-33 with no significant influence on ERK1/2 and a small increase in activation of JNKs. Inhibition of p38-MAPK signalling following pretreatment with endothelin-1 was also detected with IL-1beta, H(2)O(2) or tumour necrosis factor alpha (TNFalpha) indicating an effect intrinsic to the signalling pathway. Endothelin-1 pretreatment suppressed the increase in expression of IL-6 mRNA induced by IL-1beta and decreased the duration of expression of TNFalpha mRNA. Coupled with the general decrease in p38-MAPK signalling, we conclude that endothelin-1 attenuates the cardiac myocyte inflammatory response, potentially to confer cardioprotection.
Yndestad
Arne
A
National Heart and Lung Institute Division (Cardiovascular Sciences), Faculty of Medicine, Imperial College London, Guy Scadding Building, Dovehouse Street, London, UK.
Marshall
Andrew K
AK
Hodgkinson
Jonathan D
JD
Tham
El Li
el L
Sugden
Peter H
PH
Clerk
Angela
A
D000818:Animals; D019332:Endothelin-1 / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects*; D066298:In Vitro Techniques; D007249:Inflammation / Q000378:metabolism; D007378:Interleukins / Q000235:genetics* / Q000378:metabolism* / Q000494:pharmacology; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D019332:Endothelin-1; D007378:Interleukins; D012333:RNA, Messenger; D048051:p38 Mitogen-Activated Protein Kinases