International Immunology Advance Access originally published online on June 28, 2004
International Immunology 2004 16(8):1173-1179; doi:10.1093/intimm/dxh118
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© 2004 The Japanese Society for Immunology
ORIGINAL RESEARCH PAPERS |
The role of Tyk2, Stat1 and Stat4 in LPS-induced endotoxin signals
1 First Department of Internal Medicine, Faculty of Medicine, Kyushu University and 2 Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, 3-1-1 Maidashi, Higashi-ku, Fukuoka, Fukuoka 812-8582, Japan
3 Department of Immunology, Graduate School of Pharmaceutical Sciences, Hokkaido University, Kita-Ku Kita 12 Nishi 6, Sapporo 060-0812, Japan
4 Department of Molecular and Cellular Biology, Laboratory of Embryonic and Genetic Engineering, Medical Institute of Bioregulation, Kyushu University, Japan
5 CREST, Japan Science and Technology Corporation (JST), 4-1-8 Honcho, Kawaguchi, Saitama 332-0012, Japan
Correspondence to: K. Shimoda; E-mail: kshimoda{at}intmed1.med.kyushu-u.ac.jp
Mice lacking Tyk2, Stat1 or Stat4, which are members of the Jak–Stat signaling cascade, were resistant to LPS-induced endotoxin shock. Interestingly, Tyk2-deficient mice had higher resistance to LPS challenge than mice lacking either Stat1 or Stat4. The activation of MAPK and NF-
B by LPS, and the production of TNF-
and IL-12 after LPS injection, were not abrogated by the absence of Tyk2, Stat1 or Stat4. In Stat1-deficient mice, the induction of IFN-ß by LPS in macrophages was severely reduced, although the serum level of IFN-
was elevated after LPS injection. In contrast, in Stat-4 deficient mice, the induction of IFN-ß by LPS was normal, but the serum level of IFN- remained low after LPS injection. Interestingly, the induction of both IFN-ß and IFN- by LPS was severely reduced in Tyk2-deficient mice. Therefore, Stat1 and Stat4 independently play substantial roles in the susceptibility to LPS. Tyk2 is essential for LPS-induced endotoxin shock, and this signaling pathway is transduced by the activation of Stat1 and Stat4.
Keywords: IFN, IL-12, Jak
Transmitting editor: T. Hirano
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