Neuronal injury induces microglial production of macrophage inflammatory protein-1α in rat corticostriatal slice cultures.
Chemokines are potent chemoattractants for immune and hematopoietic cells. In the central nervous system, chemokines play an important role in inflammatory responses through activation of infiltrating leukocytes and/or resident glial cells. We previously demonstrated that N-methyl-D-aspartate (NMDA)-evoked neuronal injury induced astrocytic production of monocyte chemoattractant protein-1 (MCP-1, CCL2) via sustained activation of extracellular signal-regulated kinase (ERK) in rat organotypic slice cultures. In the present study, we examined mRNA expression and protein production of macrophage inflammatory protein-1α (MIP-1α, CCL3) induced by NMDA-evoked neuronal injury in the slice cultures. MIP-1α mRNA expression was transiently increased by NMDA treatment in a concentration-dependent manner. Double-fluorescence immunohistochemistry revealed that MIP-1α was produced predominantly in microglia. Depletion of microglial cells from the slice cultures by pretreatment with liposome-encapsulated clodronate abrogated the increase in MIP-1α mRNA expression after NMDA treatment. NMDA-induced MIP-1α mRNA expression was partially but significantly inhibited by the c-Jun N-terminal kinase inhibitor SP600125; conversely, the p38 mitogen-activated protein (MAP) kinase inhibitor SB203580 enhanced it. U0126, a MAP kinase/ERK kinase inhibitor, did not affect mRNA expression. These results, combined with our previous findings, demonstrate that NMDA-evoked neuronal injury differentially induces MIP-1α and MCP-1 production in microglia and astrocytes, respectively, through activation of different intracellular signaling pathways.
Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan.
Toshiyuki
T
Okamura
Takahiro
T
Katayama
Chihiro
C
Obinata
Yukina
Y
Iso
Yuzuho
Y
Chiba
Hayato
H
Kobayashi
Yuma
Y
Yamada
Hideyoshi
H
Harashima
Masabumi
M
Minami
D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D002450:Cell Communication / Q000502:physiology*; D054405:Chemokine CCL3 / Q000096:biosynthesis*; D007150:Immunohistochemistry; D017628:Microglia / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism / Q000473:pathology*; D009924:Organ Culture Techniques; D051381:Rats; D017208:Rats, Wistar; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology
D054405:Chemokine CCL3