Thursday, July 10, 2014

Interleukin, Microglia, and Fatigue

Induction of interleukin-1β by activated microglia is a prerequisite
for immunologically induced fatigue
Masataka Ifuku1, Shamim M. Hossain1, Mami Noda2 and Toshihiko Katafuchi1,

Article first published online: 5 JUL 2014

DOI: 10.1111/ejn.12668


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.

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