title: Interleukin-1 participates in the classical and alternative activation of microglia/macrophages after spinal cord injury.
abstract: BACKGROUND
  Microglia and macrophages (MG/MΦ) have a diverse range of functions depending on unique cytokine stimuli, and contribute to neural cell death, repair, and remodeling during central nervous system diseases. While IL-1 has been shown to exacerbate inflammation, it has also been recognized to enhance neuroregeneration. We determined the activating phenotype of MG/MΦ and the impact of IL-1 in an in vivo spinal cord injury (SCI) model of IL-1 knock-out (KO) mice. Moreover, we demonstrated the contribution of IL-1 to both the classical and alternative activation of MG in vitro using an adult MG primary culture.
  
  
  METHODS
  SCI was induced by transection of the spinal cord between the T9 and T10 vertebra in wild-type and IL-1 KO mice. Locomotor activity was monitored and lesion size was determined for 14 days. TNFα and Ym1 levels were monitored to determine the MG/MΦ activating phenotype. Primary cultures of MG were produced from adult mice, and were exposed to IFNγ or IL-4 with and without IL-1β. Moreover, cultures were exposed to IL-4 and/or IL-13 in the presence and absence of IL-1β.
  
  
  RESULTS
  The locomotor activity and lesion area of IL-1 KO mice improved significantly after SCI compared with wild-type mice. TNFα production was significantly suppressed in IL-1 KO mice. Also, Ym1, an alternative activating MG/MΦ marker, did not increase in IL-1 KO mice, suggesting that IL-1 contributes to both the classical and alternative activation of MG/MΦ. We treated primary MG cultures with IFNγ or IL-4 in the presence and absence of IL-1β. Increased nitric oxide and TNFα was present in the culture media and increased inducible NO synthase was detected in cell suspensions following co-treatment with IFNγ and IL-1β. Expression of the alternative activation markers Ym1 and arginase-1 was increased after exposure to IL-4 and further increased after co-treatment with IL-4 and IL-1β. The phenotype was not observed after exposure of cells to IL-13.
  
  
  CONCLUSIONS
  We demonstrate here in in vivo experiments that IL-1 suppressed SCI in a process mediated by the reduction of inflammatory responses. Moreover, we suggest that IL-1 participates in both the classical and alternative activation of MG in in vivo and in vitro systems.
authors.affiliation: Department of Anatomy, Showa University School of Medicine, 15-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Sato
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Ohtaki
authors.forename: Tomomi
authors.initials: T
authors.lastname: Tsumuraya
authors.forename: Dandan
authors.initials: D
authors.lastname: Song
authors.forename: Kenji
authors.initials: K
authors.lastname: Ohara
authors.forename: Masahide
authors.initials: M
authors.lastname: Asano
authors.forename: Yoichiro
authors.initials: Y
authors.lastname: Iwakura
authors.forename: Takashi
authors.initials: T
authors.lastname: Atsumi
authors.forename: Seiji
authors.initials: S
authors.lastname: Shioda
mesh_terms: D000818:Animals; D001119:Arginase / Q000378:metabolism; D039481:CD11b Antigen / Q000378:metabolism; D002478:Cells, Cultured; D002490:Central Nervous System / Q000473:pathology; D016207:Cytokines / Q000494:pharmacology; D004195:Disease Models, Animal; D004317:Doxorubicin / Q000031:analogs & derivatives / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005786:Gene Expression Regulation / Q000235:genetics; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D007375:Interleukin-1 / Q000172:deficiency / Q000378:metabolism*; D053582:Interleukin-1alpha / Q000172:deficiency; D053583:Interleukin-1beta / Q000172:deficiency; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000187:drug effects / Q000378:metabolism*; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009043:Motor Activity / Q000502:physiology; D004676:Myelin Basic Protein / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D013119:Spinal Cord Injuries / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology
chemical_list: D039481:CD11b Antigen; D016207:Cytokines; D005904:Glial Fibrillary Acidic Protein; D007375:Interleukin-1; D053582:Interleukin-1alpha; D053583:Interleukin-1beta; D008869:Microtubule-Associated Proteins; C079240:Mtap2 protein, mouse; D004676:Myelin Basic Protein; C079109:N-(3-pyridylmethyl)adriamycin; D009569:Nitric Oxide; D004317:Doxorubicin; D001119:Arginase