title: gp130 cytokines stimulate proteasomal degradation of tyrosine hydroxylase via extracellular signal regulated kinases 1 and 2.
abstract: Injury-induced cytokines act through gp130 in sympathetic neurons to suppress expression of tyrosine hydroxylase (TH) and other genes associated with noradrenergic transmission. These cytokines also trigger the local loss of TH in peri-infarct sympathetic axons after myocardial infarction, but altered gene expression cannot explain the selective loss of TH enzyme in one region of the heart. We hypothesized that inflammatory cytokines, which are highest near the infarct, stimulated local degradation of TH protein. We used cultured sympathetic neurons and neuroblastoma cells to test this hypothesis. The cytokines ciliary neurotrophic factor (CNTF) and leukemia inhibitory factor (LIF) suppressed TH content in both neurons and neuroblastoma cells. CNTF suppressed TH in a gp130-dependent manner, and decreased the half-life of TH protein by approximately 50%. CNTF stimulated the ubiquitination of TH in both neurons and neuroblastoma cells, and the proteasome inhibitors MG-132 and lactacystin prevented the CNTF-induced loss of TH protein. Inhibiting activation of extracellular signal regulated kinases 1&2 (ERK1/2) with U0126 prevented the CNTF-induced ubiquitination of TH and the associated decrease in protein half-life. Likewise, inhibiting ERK1/2 activation blunted the cytokine-stimulated loss of TH protein in sympathetic neurons, despite enhancing the loss of TH mRNA. These data suggest that gp130 cytokines stimulate proteasomal degradation of TH through an ERK1/2 dependent pathway, and may have important implications for local regulation of neurotransmission at sites of inflammation.
authors: Department of Physiology and Pharmacology, Oregon Health & Science University, Portland, Oregon, USA.
authors: Xiao
authors: X
authors: Shi
authors: Beth A
authors: BA
authors: Habecker
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002070:Butadienes / Q000494:pharmacology; D002478:Cells, Cultured; D020934:Ciliary Neurotrophic Factor / Q000494:pharmacology; D050822:Cytokine Receptor gp130 / Q000172:deficiency / Q000378:metabolism*; D004299:Dopamine beta-Hydroxylase / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005727:Ganglia, Spinal / Q000166:cytology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D006207:Half-Life; D006801:Humans; D047468:Immunoprecipitation; D053605:Leukemia Inhibitory Factor / Q000494:pharmacology; D007976:Leupeptins / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D009570:Nitriles / Q000494:pharmacology; D011247:Pregnancy; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018709:Statistics, Nonparametric; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism*; D054875:Ubiquitination / Q000187:drug effects
chemical_list: D002070:Butadienes; D020934:Ciliary Neurotrophic Factor; D004791:Enzyme Inhibitors; C494200:Il6st protein, mouse; D053605:Leukemia Inhibitory Factor; D007976:Leupeptins; D009570:Nitriles; D012333:RNA, Messenger; C113580:U 0126; D050822:Cytokine Receptor gp130; D014446:Tyrosine 3-Monooxygenase; D004299:Dopamine beta-Hydroxylase; D048052:Mitogen-Activated Protein Kinase 3; D046988:Proteasome Endopeptidase Complex; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde