Essential role of p38 mitogen-activated protein kinase in contact hypersensitivity.

Abstract

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.

• Authors: Yoko Takanami-Ohnishi, Shinya Amano, Sadao Kimura, Sachie Asada, Atsushi Utani, Masumi Maruyama, Hiroyuki Osada, Hajime Tsunoda, Yoko Irukayama-Tomobe, Katsutoshi Goto, Michael Karin, Tatsuhiko Sudo, Yoshitoshi Kasuya
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 277 Issue 40 Pg. 37896-903 (Oct 04 2002) ISSN: 0021-9258 [Print] United States
• PMID: 12138127 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Allergens
• DNA Primers
• Enzyme Inhibitors
• Imidazoles
• Pyridines
• Dinitrofluorobenzene
• Mitogen-Activated Protein Kinases
• p38 Mitogen-Activated Protein Kinases
• 4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole

Topics

• Allergens
• Animals
• Base Sequence
• DNA Primers
• Dermatitis, Contact (enzymology)
• Dinitrofluorobenzene
• Disease Models, Animal
• Enzyme Inhibitors (pharmacology)
• Female
• Imidazoles (pharmacology)
• Inflammation
• Kinetics
• Mice
• Mitogen-Activated Protein Kinases (immunology, metabolism)
• Polymerase Chain Reaction
• Pyridines (pharmacology)
• Skin (enzymology, pathology)
• p38 Mitogen-Activated Protein Kinases