The functional synergy between IL-12 and IL-2 involves p38 mitogen-activated protein kinase and is associated with the augmentation of STAT serine phosphorylation.
IL-12 and IL-2 can stimulate mitogen- or CD3-activated T cells to proliferate, produce IFN-gamma, and kill tumor cells. The magnitude of these functional responses is greatly augmented when T cells are activated by the combination of IL-12 and IL-2. Although peripheral blood T cells are largely unresponsive to these cytokines without prior activation, a small subset of CD8+ T cells (CD8+CD18bright) is strongly activated by the combination of IL-12 and IL-2. In this report we show that the functional synergy between IL-12 and IL-2 in CD8+CD18bright T cells correlates with the activation of the stress kinases, p38 mitogen-activated protein (MAP) kinase and stress-activated protein kinase (SAPK)/Jun N-terminal kinase, but not with the activation of the extracellular signal-regulated kinases. The functional synergy between IL-2 and IL-12 is also associated with a prominent increase in STAT1 and STAT3 serine phosphorylation over that observed with IL-12 or IL-2 alone. By contrast, STAT tyrosine phosphorylation is not augmented over that seen with either cytokine alone. A specific inhibitor of p38 MAP kinase completely inhibits the serine phosphorylation of STAT1 and STAT3 induced by IL-12 and IL-2 and abrogates the functional synergy between IL-12 and IL-2 without affecting STAT tyrosine phosphorylation. This suggests that p38 MAP kinase may play an important role in regulating STAT serine phosphorylation in response to the combination of IL-12 and IL-2. Furthermore, these findings indicate that the optimal activation of T cells by IL-12 and IL-2 may depend on an interaction between the p38 MAP kinase and Janus kinase/STAT signaling pathways.
Gollob
J A
JA
Department of Adult Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA. jgoll@bidmc.harvard.edu
Schnipper
C P
CP
Murphy
E A
EA
Ritz
J
J
Frank
D A
DA
D000276:Adjuvants, Immunologic / Q000502:physiology*; D000818:Animals; D018821:CD18 Antigens / Q000097:blood; D016827:CD8 Antigens / Q000097:blood; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004357:Drug Synergism; D004789:Enzyme Activation / Q000276:immunology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D018664:Interleukin-12 / Q000502:physiology*; D007376:Interleukin-2 / Q000502:physiology*; D048031:JNK Mitogen-Activated Protein Kinases; D048728:MAP Kinase Kinase Kinase 1; D051379:Mice; D020928:Mitogen-Activated Protein Kinases; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D011725:Pyridines / Q000494:pharmacology; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D012694:Serine / Q000378:metabolism*; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000201:enzymology / Q000276:immunology; D015534:Trans-Activators / Q000378:metabolism*; D014443:Tyrosine / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases
D000276:Adjuvants, Immunologic; D018821:CD18 Antigens; D016827:CD8 Antigens; D004268:DNA-Binding Proteins; D007093:Imidazoles; D007376:Interleukin-2; D011725:Pyridines; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C494080:Stat1 protein, mouse; C494087:Stat3 protein, mouse; D015534:Trans-Activators; D018664:Interleukin-12; D014443:Tyrosine; D012694:Serine; D017346:Protein Serine-Threonine Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048728:MAP Kinase Kinase Kinase 1; C482576:MAP3K1 protein, human; C482578:Map3k1 protein, mouse; C093642:SB 203580