Requirement for distinct Janus kinases and STAT proteins in T cell proliferation versus IFN-gamma production following IL-12 stimulation.
While IL-12 is known to activate JAK2 and TYK2 and induce the phosphorylation of STAT4 and STAT3, little is known regarding how the activation of these signaling molecules is related to the biologic effects of IL-12. Using an IL-12-responsive T cell clone (2D6), we investigated their requirements for proliferation and IFN-gamma production of 2D6 cells. 2D6 cells could be maintained with either IL-12 or IL-2. 2D6 lines maintained with IL-12 (2D6(IL-12)) or IL-2 (2D6(IL-2)) exhibited comparable levels of proliferation, but produced large or only small amounts of IFN-gamma, respectively, when restimulated with IL-12 after starvation of either cytokine. 2D6(IL-12) induced TYK2 and STAT4 phosphorylation. In contrast, their phosphorylation was marginally induced in 2D6(IL-2). The reduced STAT4 phosphorylation was due to a progressive decrease in the amount of STAT4 protein along with the passages in IL-2-containing medium. 2D6(IL-12) and 2D6(IL-2) similarly proliferating in response to IL-12 induced comparable levels of JAK2 activation and STAT5 phosphorylation. JAK2 was associated with STAT5, and IL-12-induced STAT5 phosphorylation was elicited in the absence of JAK3 activation. These results indicate that IL-12 has the capacity to induce/maintain STAT4 and STAT5 proteins, and that TYK2 and JAK2 activation correlate with STAT4 phosphorylation/IFN-gamma induction and STAT5 phosphorylation/cellular proliferation, respectively.
Ahn
H J
HJ
Biomedical Research Center, Osaka University Medical School, Suita, Japan.
Tomura
M
M
Yu
W G
WG
Iwasaki
M
M
Park
W R
WR
Hamaoka
T
T
Fujiwara
H
H
D000818:Animals; D002460:Cell Line; D002999:Clone Cells; D004268:DNA-Binding Proteins / Q000378:metabolism / Q000502:physiology*; D007371:Interferon-gamma / Q000096:biosynthesis*; D018664:Interleukin-12 / Q000378:metabolism / Q000494:pharmacology*; D007376:Interleukin-2 / Q000494:pharmacology; D053614:Janus Kinase 2; D008213:Lymphocyte Activation / Q000187:drug effects*; D051379:Mice; D008894:Milk Proteins; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism / Q000502:physiology*; D011506:Proteins / Q000378:metabolism / Q000502:physiology*; D011518:Proto-Oncogene Proteins; D018123:Receptors, Interleukin / Q000096:biosynthesis; D053707:Receptors, Interleukin-12; D011994:Recombinant Proteins / Q000494:pharmacology; D050796:STAT3 Transcription Factor; D050797:STAT4 Transcription Factor; D050799:STAT5 Transcription Factor; D006377:T-Lymphocytes, Helper-Inducer / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism; D053634:TYK2 Kinase; D015534:Trans-Activators / Q000378:metabolism / Q000502:physiology*; D014443:Tyrosine / Q000378:metabolism
D004268:DNA-Binding Proteins; D007376:Interleukin-2; D008894:Milk Proteins; D011506:Proteins; D011518:Proto-Oncogene Proteins; D018123:Receptors, Interleukin; D053707:Receptors, Interleukin-12; D011994:Recombinant Proteins; D050796:STAT3 Transcription Factor; D050797:STAT4 Transcription Factor; D050799:STAT5 Transcription Factor; C494087:Stat3 protein, mouse; C494091:Stat4 protein, mouse; D015534:Trans-Activators; D018664:Interleukin-12; D014443:Tyrosine; D007371:Interferon-gamma; D011505:Protein-Tyrosine Kinases; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2; D053634:TYK2 Kinase; C499356:Tyk2 protein, mouse