title: Interleukin-10 attenuates vascular responses to endothelin-1 via effects on ERK1/2-dependent pathway.
abstract: Interleukin-10 (IL-10) is an anti-inflammatory cytokine with protective actions on the vasculature. On the other hand, endothelin (ET)-1 has potent vasoconstrictor, mitogenic, and proinflammatory activities, which have been implicated in the pathophysiology of a number of cardiovascular diseases. We hypothesized that, in a condition where ET-1 expression is upregulated, i.e., on infusion of TNF-alpha, IL-10 confers vascular protection from ET-1-induced injury. Aortic rings and first-order mesenteric arteries from male C57BL/6 (WT) and IL-10-knockout (IL-10(-/-)) mice were treated with human recombinant TNF-alpha (220 ng x kg(-1) x day(-1)) or vehicle (saline) for 14 days. TNF-alpha infusion significantly increased blood pressure in IL-10(-/-), but not WT, mice. TNF-alpha augmented vascular ET-1 mRNA expression in arteries from WT and IL-10(-/-) mice. ET type A (ET(A)) receptor expression was increased in arteries from IL-10(-/-) mice, and TNF-alpha infusion did not change vascular ET(A) receptor expression in control or IL-10(-/-) mice. Aorta and mesenteric arteries from TNF-alpha-infused IL-10(-/-) mice displayed increased contractile responses to ET-1, but not the ET type B receptor agonist IRL-1620. The ET(A) receptor antagonist atrasentan completely abolished responses to ET-1 in aorta and mesenteric vessels, whereas the ERK1/2 inhibitor PD-98059 abrogated increased contractions to ET-1 in arteries from TNF-alpha-infused IL-10(-/-) mice. Infusion of TNF-alpha, as well as knockdown of IL-10 (IL-10(-/-)), induced an increase in total and phosphorylated ERK1/2. These data demonstrate that IL-10 counteracts ET(A)-mediated vascular responses to ET-1, as well as activation of the ERK1/2 pathway.
authors.affiliation: Department of Physiology, Medical College of Georgia, Augusta, GA 30912-3000, USA. fgiachini@mcg.edu
authors.forename: Fernanda R C
authors.initials: FR
authors.lastname: Giachini
authors.forename: Saiprasad M
authors.initials: SM
authors.lastname: Zemse
authors.forename: Fernando S
authors.initials: FS
authors.lastname: Carneiro
authors.forename: Victor V
authors.initials: VV
authors.lastname: Lima
authors.forename: Zidonia N
authors.initials: ZN
authors.lastname: Carneiro
authors.forename: Glaucia E
authors.initials: GE
authors.lastname: Callera
authors.forename: Adviye
authors.initials: A
authors.lastname: Ergul
authors.forename: R Clinton
authors.initials: RC
authors.lastname: Webb
authors.forename: Rita C
authors.initials: RC
authors.lastname: Tostes
mesh_terms: D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000201:enzymology*; D000077868:Atrasentan; D001794:Blood Pressure; D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1 / Q000235:genetics / Q000378:metabolism*; D016232:Endothelins / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D015918:Infusion Pumps, Implantable; D016753:Interleukin-10 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects / Q000201:enzymology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010446:Peptide Fragments / Q000494:pharmacology; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011759:Pyrrolidines / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D044022:Receptor, Endothelin A / Q000378:metabolism; D044023:Receptor, Endothelin B / Q000819:agonists / Q000378:metabolism; D011994:Recombinant Proteins / Q000008:administration & dosage; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage; D014661:Vasoconstriction
chemical_list: D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1; D016232:Endothelins; D005419:Flavonoids; D010446:Peptide Fragments; D047428:Protein Kinase Inhibitors; D011759:Pyrrolidines; D012333:RNA, Messenger; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; C074308:sovateltide; D016753:Interleukin-10; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; D000077868:Atrasentan