Urocortin modulates inflammatory response and neurotoxicity induced by microglial activation.
Microglia are the major inflammatory cells in the brain. Recent studies have highlighted the reciprocal roles of other brain cells in modulating the microglial inflammatory responses. Urocortin (UCN) is a member of the corticotropin-releasing hormone (CRH) family of neuropeptides that function to regulate stress responses. In the present study, we demonstrated that expression of UCN in rat substantia nigra was found to be localized principally to dopaminergic neurons. In cell culture models, the CRH receptors were expressed in microglia, and CRHR expression was up-regulated by treatment with LPS. Thus, it might be proposed that UCN regulates cellular communication between dopaminergic neurons and microglia. We show that femtomolar concentrations of UCN could inhibit LPS-induced TNF-alpha production in cultured microglia. Investigation of the underlying signaling pathway that mediated the anti-inflammatory effect of UCN the involved PI3K/Akt and glycogen synthase kinase-3beta pathway, but not cAMP pathway. Furthermore, UCN protected dopaminergic neurons against LPS-induced neurotoxicity by inhibiting microglial activation in LPS-treated mesencephalic neuron-glia cultures. These results suggest that endogenous UCN and its receptors might be involved in a complex network of paracrine interaction between dopaminergic neurons and glia.
Wang
Mei-Jen
MJ
Neuro-Medical Scientific Center, Buddhist Tzu-Chi General Hospital, Tzu-Chi College of Technology, Hualien, Taiwan, Republic of China. mjwang@tzuchi.com.tw
Lin
Shinn-Zong
SZ
Kuo
Jon-Son
JS
Huang
Hsin-Yi
HY
Tzeng
Shih-Fang
SF
Liao
Chia-Hsin
CH
Chen
Der-Cherng
DC
Chen
Wu-Fu
WF
D000375:Aging / Q000502:physiology; D000818:Animals; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D002867:Chromones / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D004789:Enzyme Activation; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D017628:Microglia / Q000187:drug effects / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009025:Morpholines / Q000494:pharmacology; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D018019:Receptors, Corticotropin-Releasing Hormone / Q000378:metabolism; D013378:Substantia Nigra / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D054832:Urocortins / Q000378:metabolism*
D002867:Chromones; D000242:Cyclic AMP; D038362:Glycogen Synthase Kinase 3; D008070:Lipopolysaccharides; D020928:Mitogen-Activated Protein Kinases; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D018019:Receptors, Corticotropin-Releasing Hormone; D014409:Tumor Necrosis Factor-alpha; D054832:Urocortins; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one