title: RANTES has a potential to play a neuroprotective role in an autocrine/paracrine manner after ischemic stroke.
abstract: Regulated upon Activation, Normal T-cell Expressed, and Secreted (RANTES) is a well-known pro-inflammatory chemokine and its role in ischemic stroke remains controversial. We examined the significance of RANTES in ischemic stroke and aimed to elucidate the direct effect of RANTES on neurons. Plasma concentrations of major C-C chemokines, including RANTES, and neurotrophic factors were examined in 171 ischemic stroke patients and age- and gender- matched healthy subjects. Plasma concentrations of RANTES at day 0 after onset were significantly elevated in stroke patients, compared with controls, and were highly correlated with those of BDNF, EGF, and VEGF. In a mouse middle cerebral artery occlusion model (MCAO), plasma RANTES was significantly elevated and the expression of RANTES was markedly upregulated in neurons particularly in peri-infarct areas. The expression of CCR3 and CCR5, receptors for RANTES, was also induced in neurons, while another receptor, CCR1, was observed in vascular cells, in peri-infarct areas after MCAO. We examined the effects of RANTES on differentiated PC12 cells, a model of neuronal cells. Treatment with RANTES induced the activation of Akt and Erk1/2, and attenuated the cleavage of caspase-3 in the cells. RANTES increased the expression of BDNF, EGF, and VEGF in the cells. Moreover, RANTES maintained the number of cells under serum free conditions. The RANTES-mediated upregulation of neurotrophic factors and cell survival were significantly attenuated by the inhibition of Akt or Erk1/2. Taken together, RANTES is an interesting chemokine that is produced from neurons after ischemic stroke and has the potential to protect neurons directly or indirectly through the production of neurotrophic factors in peri-infarct areas.
authors.affiliation: Department of Clinical Science and Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Himiko
authors.initials: H
authors.lastname: Tokami
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Ago
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Sugimori
authors.forename: Junya
authors.initials: J
authors.lastname: Kuroda
authors.forename: Hideto
authors.initials: H
authors.lastname: Awano
authors.forename: Kazuo
authors.initials: K
authors.lastname: Suzuki
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Kiyohara
authors.forename: Masahiro
authors.initials: M
authors.lastname: Kamouchi
authors.forename: Takanari
authors.initials: T
authors.lastname: Kitazono
mesh_terms: D000368:Aged; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002545:Brain Ischemia; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D016022:Case-Control Studies; D053148:Caspase 3 / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D018946:Chemokine CCL5 / Q000378:metabolism / Q000627:therapeutic use*; D019742:Chemokines, CC / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D020932:Nerve Growth Factor / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D016716:PC12 Cells; D051381:Rats; D015398:Signal Transduction / Q000502:physiology; D020521:Stroke / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D013997:Time Factors
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D018946:Chemokine CCL5; D019742:Chemokines, CC; D004791:Enzyme Inhibitors; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D020932:Nerve Growth Factor; D053148:Caspase 3