Regulation of noradrenergic function by inflammatory cytokines and depolarization.
Although the sympathetic neurons innervating the heart are exposed to the inflammatory cytokines cardiotrophin-1 (CT-1), interleukin-6 (IL-6) and tumor necrosis factor alpha (TNFalpha) after myocardial infarction, the effects of these cytokines on noradrenergic function are not well understood. We used cultured sympathetic neurons to investigate the effects of these cytokines on catecholamine content, the tyrosine hydroxylase co-factor, tetrahydrobiopterin (BH4), and norepinephrine (NE) uptake. CT-1, but not IL-6 or TNFalpha, suppressed NE uptake and catecholamines in these neurons, whereas CT-1 and, to a lesser extent, IL-6 decreased BH4 content. CT-1 exerted these effects by decreasing tyrosine hydroxylase, GTP cyclohydrolase (GCH) and NE transporter mRNAs, while IL-6 lowered only GCH mRNA. The neurons innervating the heart are also activated by the central nervous system after myocardial infarction. We examined the combined effect of depolarization and cytokines on noradrenergic function. In CT-1-treated cells, depolarization caused a small increase in BH4 and NE uptake, and a large increase in catecholamines. These changes were accompanied by increased TH, GCH and NE transporter mRNAs. CT-1 and depolarization regulate expression of noradrenergic properties in an opposing manner, and the combined treatment results in elevated cellular catecholamines and decreased NE uptake relative to control cells.
Li
Wei
W
Department of Physiology & Pharmacology, Oregon Health & Science University School of Medicine, Portland, Oregon 97239, USA.
Knowlton
David
D
Woodward
William R
WR
Habecker
Beth A
BA
D000818:Animals; D001708:Biopterins / Q000031:analogs & derivatives* / Q000378:metabolism; D002395:Catecholamines / Q000378:metabolism; D016764:Cell Polarity / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D020934:Ciliary Neurotrophic Factor / Q000494:pharmacology; D016207:Cytokines / Q000494:pharmacology / Q000502:physiology*; D006136:GTP Cyclohydrolase / Q000235:genetics; D006131:Growth Inhibitors / Q000494:pharmacology; D006321:Heart / Q000294:innervation; D018836:Inflammation Mediators / Q000494:pharmacology / Q000502:physiology*; D015850:Interleukin-6 / Q000494:pharmacology / Q000502:physiology; D053605:Leukemia Inhibitory Factor; D008222:Lymphokines / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D009638:Norepinephrine / Q000378:metabolism* / Q000493:pharmacokinetics; D050484:Norepinephrine Plasma Membrane Transport Proteins; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013564:Sympathetic Nervous System / Q000166:cytology; D027981:Symporters / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology / Q000502:physiology; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics
D002395:Catecholamines; D020934:Ciliary Neurotrophic Factor; D016207:Cytokines; D006131:Growth Inhibitors; D018836:Inflammation Mediators; D015850:Interleukin-6; D053605:Leukemia Inhibitory Factor; D008222:Lymphokines; D050484:Norepinephrine Plasma Membrane Transport Proteins; D012333:RNA, Messenger; C493226:Slc6a2 protein, rat; D027981:Symporters; D014409:Tumor Necrosis Factor-alpha; D001708:Biopterins; C092073:cardiotrophin 1; D014446:Tyrosine 3-Monooxygenase; D006136:GTP Cyclohydrolase; C003402:sapropterin; D009638:Norepinephrine