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Blood, 15 March 2002, Vol. 99, No. 6, pp. 2094-2099
IMMUNOBIOLOGY
Partial impairment of interleukin-12 (IL-12) and IL-18 signaling
in Tyk2-deficient mice
Kazuya Shimoda,
Hiroko Tsutsui,
Kenichi Aoki,
Kouji Kato,
Tadashi Matsuda,
Akihiko Numata,
Ken Takase,
Tetsuya Yamamoto,
Hideyuki Nukina,
Tomoaki Hoshino,
Yoshinobu Asano,
Hisashi Gondo,
Takashi Okamura,
Seiichi Okamura,
Kei-Ichi Nakayama,
Kenji Nakanishi,
Yoshiyuki Niho, and
Mine Harada
From the First Department of Internal Medicine, Faculty
of Medicine, Kyushu University, Higashi-ku, Fukuoka, Japan; Medicine
and Biosystemic Science, Kyushu University Graduate School of Medical
Sciences, Higashi-ku, Fukuoka, Japan; Department of Immunology and
Medical Zoology, Laboratory Host Defences Institute for Advanced
Medical Sciences, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan;
Department of Immunology, Graduate School of Pharmaceutical
Sciences, Hokkaido University, Japan; Pharmacosomatic
Medicine, Faculty of Medicine, Kyushu University, Higashi-ku, Fukuoka,
Japan; First Department of Internal Medicine, Kurume University School
of Medicine, Kurume, Fukuoka, Japan; Hematology Department, Internal
Medicine, Kyushu Medical Center, Chuo-ku, Fukuoka, Fukuoka, Japan;
Department of Molecular and Cellular Biology, Laboratory of Embryonic
and Genetic Engineering, Medical Institute of Bioregulation, Kyushu
University, Higashi-ku, Fukuoka, Japan; CREST, Japan Science and
Technology Corporation (JST), Kawaguchi, Saitama, Japan; and Chihaya
Hospital, Higashi-ku, Fukuoka, Japan.
Tyk2 is activated in response to interleukin-12 (IL-12)
and is essential for IL-12-induced T-cell function, including
interferon- (IFN-) production and Th1 cell differentiation.
Because IL-12 is a stimulatory factor for natural killer (NK)
cell-mediated cytotoxicity, we examined whether tyk2 is required for
IL-12-induced NK cell activity. IL-12-induced NK cell activity in
cells from tyk2-deficient mice was drastically reduced compared to that
in cells from wild-type mice. IL-18 shares its biologic functions with
IL-12. However, the molecular mechanism of IL-18 signaling, which
activates an IL-1 receptor-associated kinase and nuclear translocation of nuclear factor- B, is different from that of IL-12.
We next examined whether biologic functions induced by IL-18 are
affected by the absence of tyk2. NK cell activity and IFN-
production induced by IL-18 were reduced by the absence of tyk2.
Moreover, the synergistic effect of IL-12 and IL-18 for the production
of IFN- was also abrogated by the absence of tyk2. This was
partially due to the absence of any up-regulation of the IL-18 receptor
treated with IL-12, and it might suggest the presence of the cross-talk
between Jak-Stat and mitogen-activated protein kinase pathways in
cytokine signaling.
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