Interferon-gamma induces microglial-activation-induced cell death: a hypothetical mechanism of relapse and remission in multiple sclerosis.
Relapse and remission are characteristics of multiple sclerosis (MS). The underlying mechanisms, however, remain uncertain. Interferon-gamma (IFN-gamma) disturbs the immunological privilege of the central nervous system (CNS) by inducing major histocompatibility complex antigen expression in CNS cells and activating microglia to become antigen-presenting and effector cells. Thus, IFN-gamma and microglia are thought to play important roles in the initiation and development of MS. Here, we show that IFN-gamma induces microglial apoptosis as the activation-induced cell death. This microglial apoptosis was associated with the up-regulation of pro-apoptosis proteins, especially Bax. Microglial apoptosis was also observed in peak EAE mice, but not in early EAE mice. Therefore, IFN-gamma may act on microglia as part of a self-limiting negative feedback system. The activation and subsequent death of microglia induced by IFN-gamma may play pivotal roles in the mechanism of MS relapse and remission.
Takeuchi
Hideyuki
H
Department of Neuroimmunology, Research Institute of Environmental Medicine, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan. htake@riem.nagoya-u.ac.jp
Wang
Jinyan
J
Kawanokuchi
Jun
J
Mitsuma
Norimasa
N
Mizuno
Tetsuya
T
Suzumura
Akio
A
D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000276:immunology*; D002478:Cells, Cultured; D002490:Central Nervous System / Q000276:immunology / Q000473:pathology / Q000503:physiopathology*; D018920:Coculture Techniques; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology; D025461:Feedback, Physiological / Q000276:immunology; D005911:Gliosis / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology*; D020287:In Situ Nick-End Labeling; D007371:Interferon-gamma / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000276:immunology* / Q000378:metabolism; D008959:Models, Neurological; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology*; D013116:Spinal Cord / Q000276:immunology / Q000473:pathology / Q000503:physiopathology; D015854:Up-Regulation / Q000276:immunology; D051028:bcl-2-Associated X Protein / Q000276:immunology
D051028:bcl-2-Associated X Protein; D007371:Interferon-gamma