Differential requirements for JAK2 and TYK2 in T cell proliferation and IFN‐γ production induced by IL‐12 alone or together with IL‐18

• Published in: European journal of immunology 2003-01, Vol.33 (1), p.243-251
• Main Authors: Sugimoto, Naotoshi, Nakahira, Masakiyo, Ahn, Hyun‐Jong, Micallef, Mark, Hamaoka, Toshiyuki, Kurimoto, Masashi, Fujiwara, Hiromi
• Format: Article
• Language: English
• Subjects: Animals; Cell Division - drug effects; Cell Line; Cytokine; DNA-Binding Proteins - metabolism; Enzyme Activation - drug effects; Gene Expression Regulation - drug effects; Interferon-gamma - metabolism; Interleukin-12 - pharmacology; Interleukin-18 - pharmacology; Janus Kinase 2; Mice; Milk Proteins; Protein-Tyrosine Kinases - metabolism; Proteins - metabolism; Proto-Oncogene Proteins; Signal transduction; STAT3 Transcription Factor; STAT4 Transcription Factor; STAT5 Transcription Factor; T-Lymphocytes - cytology; T-Lymphocytes - drug effects; T-Lymphocytes - enzymology; T-Lymphocytes - metabolism; Trans-Activators - metabolism; Transcription factor; TYK2 Kinase; Tyrphostins - pharmacology; T lymphocyte
• ISSN: 0014-2980; 1521-4141
• DOI: 10.1002/immu.200390027

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‐γ 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‐γ production. IL‐18, but not IL‐12, induced activator protein‐1 (AP‐1) responsible for high levels of IFN‐γ 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‐γ 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‐γ expression that is mediated by IL‐12 alone and enhanced synergistically by combination with IL‐18.