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J. Biol. Chem., Vol. 277, Issue 40, 37896-37903, October 4, 2002
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From the a Department of Biochemistry and Molecular
Pharmacology and the f Department of Dermatology, Graduate
School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku,
Chiba 260-8670, g Antibiotics Laboratory, RIKEN, 2-1 Hirosawa,
Wako, Saitama 351-0198, e Center for the Tsukuba Advanced
Research Alliance, b Department of Obstetrics and Gynecology and
h Department of Cardiology, Institute of Clinical Sciences, and
c Department of Pharmacology, Institute of Basic Medical
Sciences, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan,
and i Laboratory of Gene Regulation and Signal Transduction,
Department of Pharmacology, University of California, San Diego,
La Jolla, California 92093
The present study was designed to elucidate the
role of p38 mitogen-activated protein kinase (p38) in the pathogenesis
of inflammation, using a mouse contact hypersensitivity (CHS) model induced by 2,4-dinitro-1-fluorobenzene (DNFB). Ear swelling was induced
by challenge with DNFB, accompanied by infiltration of mononuclear
cells, neutrophils, and eosinophils and a marked increase in mRNA
levels of cytokines such as interleukin (IL)-2, interferon (IFN)-
Essential Role of p38 Mitogen-activated Protein Kinase in Contact
Hypersensitivity*
,
IL-4, IL-5, IL-1
, IL-18, and tumor necrosis factor-
in the
challenged ear skin. Both ear swelling and the number of infiltrated
cells in DNFB-challenged ear skin were significantly inhibited by
treatment with SB202190, a p38 inhibitor. Furthermore, the DNFB-induced
expression of all cytokines except IL-4 was significantly inhibited by
treatment with SB202190. Ribonuclease protection assay revealed that
the mRNA levels of chemokines such as IP-10 and MCP-1 in ear skin
were markedly increased at 24 h after challenge with DNFB. The
induction of these chemokines was significantly inhibited by treatment
with SB202190. In p38 +/
mice, both ear swelling and infiltration
of cells induced by DNFB were reduced compared with those in wild-type
mice. However, induction of cytokines by DNFB was also observed in
p38 +/ mice, although the induction of IFN-, IL-5, and IL-18
was typically reduced compared with that in wild-type mice. Challenge
with DNFB slightly induced IP-10 and MCP-1 mRNA in p38 +/
mice, with weaker signals than those in SB202190-treated wild-type
mice. These results suggest that p38 plays a key role in CHS and is an
important target for the treatment of CHS.
*
This work was supported in part by a grant-in-aid for
Scientific Research from the Ministry of Education, Science, Sports and
Culture of Japan, by a Grant-in-aid for "Research for the Future
Program" RFTF96I00202 from the Japan Society for Promotion of
Science, and by a Grant from the Cosmetology Research Foundation J-01-08.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.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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