Essential role of p38 mitogen-activated protein kinase in contact hypersensitivity.
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)-gamma, IL-4, IL-5, IL-1beta, IL-18, and tumor necrosis factor-alpha 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 p38alpha +/- 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 p38alpha +/- mice, although the induction of IFN-gamma, 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 p38alpha +/- 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.
Department of Biochemistry and Molecular Pharmacology, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, Japan.
Yoko
Y
Takanami-Ohnishi
Shinya
S
Amano
Sadao
S
Kimura
Sachie
S
Asada
Atsushi
A
Utani
Masumi
M
Maruyama
Hiroyuki
H
Osada
Hajime
H
Tsunoda
Yoko
Y
Irukayama-Tomobe
Katsutoshi
K
Goto
Michael
M
Karin
Tatsuhiko
T
Sudo
Yoshitoshi
Y
Kasuya
D000485:Allergens; D000818:Animals; D001483:Base Sequence; D017931:DNA Primers; D003877:Dermatitis, Contact / Q000201:enzymology*; D004139:Dinitrofluorobenzene; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D007093:Imidazoles / Q000494:pharmacology; D007249:Inflammation; D007700:Kinetics; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000276:immunology* / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D011725:Pyridines / Q000494:pharmacology; D012867:Skin / Q000201:enzymology / Q000473:pathology*; D048051:p38 Mitogen-Activated Protein Kinases
D000485:Allergens; D017931:DNA Primers; D004791:Enzyme Inhibitors; D007093:Imidazoles; D011725:Pyridines; D004139:Dinitrofluorobenzene; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C090942:4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole