Differential requirements for JAK2 and TYK2 in T cell proliferation and IFN-gamma production induced by IL-12 alone or together with IL-18.
IL-12 activates TYK2 and Janus kinase (JAK)-2 to induce the phosphorylation of various signal transducers and activators of transcription (STAT) proteins. However, little is known regarding how these JAK exhibit the distinct biological effects of IL-12. Using two JAK inhibitors, tyrphostin A1 (A1) for TYK2 and tyrphostin B42 (B42) for JAK2, we investigated the involvement of JAK2 and TYK2 in IL-12-induced T cell proliferation and IFN-gamma production. B42, but not A1, inhibited T cell proliferation along with down-regulation of IL-12-induced c-Myc expression and STAT5 phosphorylation. In contrast, A1 but not B42 inhibited STAT4/STAT3 phosphorylation and IFN-gamma production. IL-18, but not IL-12, induced activator protein-1 (AP-1) responsible for high levels of IFN-gamma promoter activation. However, this IL-18 effect depended on the interaction of AP-1 with STAT4. A1 prevented AP-1 binding by inhibiting STAT4 involvement and down-regulated synergistic IFN-gamma promoter activation. These results indicate that JAK2 activation is required for IL-12-mediated T cell growth, whereas the TYK2-STAT4 signaling pathway is critical for IFN-gamma expression that is mediated by IL-12 alone and enhanced synergistically by combination with IL-18.
Sugimoto
Naotoshi
N
Department of Oncology, Osaka University Graduate School of Medicine, Osaka, Japan.
Nakahira
Masakiyo
M
Ahn
Hyun-Jong
HJ
Micallef
Mark
M
Hamaoka
Toshiyuki
T
Kurimoto
Masashi
M
Fujiwara
Hiromi
H
D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D007371:Interferon-gamma / Q000378:metabolism*; D018664:Interleukin-12 / Q000494:pharmacology*; D020382:Interleukin-18 / Q000494:pharmacology*; D053614:Janus Kinase 2; D051379:Mice; D008894:Milk Proteins; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism*; D011518:Proto-Oncogene Proteins; D050796:STAT3 Transcription Factor; D050797:STAT4 Transcription Factor; D050799:STAT5 Transcription Factor; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism*; D053634:TYK2 Kinase; D015534:Trans-Activators / Q000378:metabolism; D020032:Tyrphostins / Q000494:pharmacology
D004268:DNA-Binding Proteins; D020382:Interleukin-18; D008894:Milk Proteins; D011506:Proteins; D011518:Proto-Oncogene Proteins; D050796:STAT3 Transcription Factor; D050797:STAT4 Transcription Factor; D050799:STAT5 Transcription Factor; C494087:Stat3 protein, mouse; C494091:Stat4 protein, mouse; D015534:Trans-Activators; D020032:Tyrphostins; D018664:Interleukin-12; D007371:Interferon-gamma; D011505:Protein-Tyrosine Kinases; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2; D053634:TYK2 Kinase; C499356:Tyk2 protein, mouse