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.
National Heart and Lung Institute Division (Cardiovascular Sciences), Faculty of Medicine, Imperial College London, Guy Scadding Building, Dovehouse Street, London, UK.
Arne
A
Yndestad
Andrew K
AK
Marshall
Jonathan D
JD
Hodgkinson
El Li
el L
Tham
Peter H
PH
Sugden
Angela
A
Clerk
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