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J. Biol. Chem., Vol. 277, Issue 43, 40594-40601, October 25, 2002
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From the Department of Pharmacology, School of Medicine, Ajou
University, Suwon 442-721, Korea
Neuronal cell membranes are particularly rich in
gangliosides, which play important roles in brain physiology and
pathology. Previously, we reported that gangliosides could act as
microglial activators and are thus likely to participate in many
neuronal diseases. In the present study we provide evidence that
JAK-STAT inflammatory signaling mediates gangliosides-stimulated
microglial activation. Both in rat primary microglia and murine BV2
microglial cells, gangliosides stimulated nuclear factor binding to
GAS/ISRE elements, which are known to be STAT-binding sites. Consistent with this, gangliosides rapidly activated JAK1 and JAK2 and induced phosphorylation of STAT1 and STAT3. In addition, gangliosides increased
transcription of the inflammation-associated genes inducible nitric-oxide syn- thase, ICAM-1, and MCP-1, which are
reported to contain STAT-binding elements in their promoter regions.
AG490, a JAK inhibitor, reduced induction of these genes, nuclear
factor binding activity, and activation of STAT1 and -3 in
gangliosides-treated microglia. AG490 also inhibited
gangliosides-induced release of nitric oxide, an inflammation hallmark.
Furthermore, AG490 markedly reduced activation of ERK1/2 MAPK,
indicating that ERKs act downstream of JAK-STAT signaling during
microglial activation. However, AG490 did not affect activation of p38
MAPK. We also report that the sialic acid residues present on
gangliosides may be one of the essential components in activation of
JAK-STAT signaling. The present study indicates that JAK-STAT signaling
is an early event in gangliosides-induced brain inflammatory responses.
JAK-STAT Signaling Mediates Gangliosides-induced Inflammatory
Responses in Brain Microglial Cells*
,,
*
This work was supported by Grant R01-2000-00164 from the
Basic Research Program of the KOSEF and by Critical Technology
21[01-J-LF-B-77 Grant from the Korea Ministry of Science and
Technology (to I. J.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Both authors contributed equally to this paper.
§
To whom correspondence should be addressed: Dept. of Pharmacology,
School of Medicine, Ajou University, Suwon, 442-721, Korea. Tel.:
82-31-219-5061; Fax: 82-31-219-5069; E-mail: jouilo@madang.ajou.ac. kr.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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