Partial impairment of interleukin-12 (IL-12) and IL-18 signaling in Tyk2-deficient mice.
Tyk2 is activated in response to interleukin-12 (IL-12) and is essential for IL-12-induced T-cell function, including interferon-gamma (IFN-gamma) 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-kappaB, 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-gamma 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-gamma 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.
Shimoda
Kazuya
K
First Department of Internal Medicine, Faculty of Medicine, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. kshimoda@intmed1.med.kyushu-u.ac.jp
Tsutsui
Hiroko
H
Aoki
Kenichi
K
Kato
Kouji
K
Matsuda
Tadashi
T
Numata
Akihiko
A
Takase
Ken
K
Yamamoto
Tetsuya
T
Nukina
Hideyuki
H
Hoshino
Tomoaki
T
Asano
Yoshinobu
Y
Gondo
Hisashi
H
Okamura
Takashi
T
Okamura
Seiichi
S
Nakayama
Kei-Ichi
K
Nakanishi
Kenji
K
Niho
Yoshiyuki
Y
Harada
Mine
M
D000818:Animals; D005786:Gene Expression Regulation / Q000187:drug effects; D007371:Interferon-gamma / Q000096:biosynthesis / Q000187:drug effects; D018664:Interleukin-12 / Q000494:pharmacology / Q000502:physiology*; D020382:Interleukin-18 / Q000494:pharmacology / Q000502:physiology*; D053727:Interleukin-18 Receptor alpha Subunit; D007694:Killer Cells, Natural / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D018655:Lymphocyte Count; D051379:Mice; D018345:Mice, Knockout; D011505:Protein-Tyrosine Kinases; D011506:Proteins / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D018123:Receptors, Interleukin / Q000378:metabolism; D053724:Receptors, Interleukin-18; D015398:Signal Transduction / Q000187:drug effects*; D053634:TYK2 Kinase
C508573:Il18r1 protein, mouse; D020382:Interleukin-18; D053727:Interleukin-18 Receptor alpha Subunit; D011506:Proteins; D018123:Receptors, Interleukin; D053724:Receptors, Interleukin-18; D018664:Interleukin-12; D007371:Interferon-gamma; D011505:Protein-Tyrosine Kinases; D053634:TYK2 Kinase; C499356:Tyk2 protein, mouse