title: Induction of interleukin-1β by activated microglia is a prerequisite for immunologically induced fatigue.
abstract: We previously reported that an intraperitoneal (i.p.) injection of synthetic double-stranded RNA, polyriboinosinic:polyribocytidylic acid (poly-I:C), produced prolonged fatigue in rats, which might serve as a model for chronic fatigue syndrome. The poly-I:C-induced fatigue was associated with serotonin transporter (5-HTT) overexpression in the prefrontal cortex (PFC), a brain region that has been suggested to be critical for fatigue sensation. In the present study, we demonstrated that microglial activation in the PFC was important for poly-I:C-induced fatigue in rats, as pretreatment with minocycline, an inhibitor of microglial activation, prevented the decrease in running wheel activity. Poly-I:C injection increased the microglial interleukin (IL)-1β expression in the PFC. An intracerebroventricular (i.c.v.) injection of IL-1β neutralising antibody limited the poly-I:C-induced decrease in activity, whereas IL-1β (i.c.v.) reduced the activity in a dose-dependent manner. 5-HTT expression was enhanced by IL-1β in primary cultured astrocytes but not in microglia. Poly-I:C injection (i.p.) caused an increase in 5-HTT expression in astrocytes in the PFC of the rat, which was inhibited by pretreatment with minocycline (i.p.) and rat recombinant IL-1 receptor antagonist (i.c.v.). Poly-I:C injection (i.p.) led to a breakdown of the blood-brain barrier and enhanced Toll-like receptor 3 signaling in the brain. Furthermore, direct application of poly-I:C enhanced IL-1β expression in primary microglia. We therefore propose that poly-I:C-induced microglial activation, which may be at least partly caused by a direct action of poly-I:C, enhances IL-1β expression. Then, IL-1β induces 5-HTT expression in astrocytes, resulting in the immunologically induced fatigue.
authors.affiliation: Department of Integrative Physiology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.
authors.forename: Masataka
authors.initials: M
authors.lastname: Ifuku
authors.forename: Shamim M
authors.initials: SM
authors.lastname: Hossain
authors.forename: Mami
authors.initials: M
authors.lastname: Noda
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Katafuchi
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism; D005221:Fatigue / Q000139:chemically induced / Q000276:immunology*; D053583:Interleukin-1beta / Q000378:metabolism*; D008297:Male; D017628:Microglia / Q000187:drug effects / Q000378:metabolism*; D008911:Minocycline / Q000494:pharmacology; D009043:Motor Activity / Q000187:drug effects; D011070:Poly I-C / Q000633:toxicity; D017397:Prefrontal Cortex / Q000276:immunology* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism
chemical_list: D053583:Interleukin-1beta; D050486:Serotonin Plasma Membrane Transport Proteins; C493232:Slc6a4 protein, rat; D008911:Minocycline; D011070:Poly I-C
keywords: Toll-like receptor; blood-brain barrier; chronic fatigue syndrome; poly-I:C; serotonin transporter