IL-12 Provides Proliferation and Survival Signals to Murine CD4+ T Cells Through Phosphatidylinositol 3-Kinase/Akt Signaling Pathway1

IL-12 is a pleiotropic cytokine that plays an important role in innate and adaptive immunity. IL-12 induces T cell proliferation and IFN-γ secretion from activated T cells. It was also reported that IL-12 prevents apoptosis of CD4+ T cells. However, the signaling mechanism that regulates these IL-12-induced responses is poorly understood yet. In this study, we demonstrated that IL-12 activates phosphatidylinositol 3-kinase (PI3K)/Akt pathway in murine CD4+ T cells, and that this signaling pathway is required for IL-12-induced T cell proliferation and antiapoptotic function, but not for IFN-γ induction. Through PI3K/Akt pathway, IL-12 up-regulates the expression of cell cycle-related molecule such as cyclin D3, and antiapoptotic molecules such as Bcl-2 and cellular inhibitors of apoptosis proteins-2, followed by down-regulation of active caspase-3. These results suggest that PI3K/Akt pathway is critical for mediating IL-12-induced CD4+ T cell responses such as T cell proliferation and survival.

[1]  S. Ha,et al.  A Novel Function of Phosphorothioate Oligodeoxynucleotides as Chemoattractants for Primary Macrophages1 , 2001, The Journal of Immunology.

[2]  G. V. van Seventer,et al.  IL-12 Decreases Activation-Induced Cell Death in Human Naive Th Cells Costimulated by Intercellular Adhesion Molecule-1. I. IL-12 Alters Caspase Processing and Inhibits Enzyme Function1 , 2001, The Journal of Immunology.

[3]  D. Cantrell.  Phosphoinositide 3-kinase signalling pathways. , 2001, Journal of cell science.

[4]  J. Gutkind,et al.  Importance of the MKK6/p38 pathway for interleukin-12-induced STAT4 serine phosphorylation and transcriptional activity. , 2000, Blood.

[5]  M. Kaplan,et al.  The p38 Mitogen-Activated Protein Kinase Is Required for IL-12-Induced IFN-γ Expression1 , 2000, The Journal of Immunology.

[6]  Michael J. Parsons,et al.  Protein Kinase B Regulates T Lymphocyte Survival, Nuclear Factor κb Activation, and Bcl-XL Levels in Vivo , 2000, The Journal of experimental medicine.

[7]  D. Cantrell,et al.  IL‐12 selectively regulates STAT4 via phosphatidylinositol 3‐kinase and Ras‐independent signal transduction pathways , 2000, European journal of immunology.

[8]  Pumin Zhang,et al.  The cell cycle and development: redundant roles of cell cycle regulators. , 1999, Current opinion in cell biology.

[9]  S. R. Datta,et al.  Cellular survival: a play in three Akts. , 1999, Genes & development.

[10]  B. Ludviksson,et al.  Extinction of IL-12 signaling promotes Fas-mediated apoptosis of antigen-specific T cells. , 1999, Journal of immunology.

[11]  C. Du,et al.  Tyrphostin B42 inhibits IL-12-induced tyrosine phosphorylation and activation of Janus kinase-2 and prevents experimental allergic encephalomyelitis. , 1999, Journal of immunology.

[12]  J. Ritz,et al.  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. , 1999, Journal of immunology.

[13]  C. Y. Wang,et al.  NF-kappaB antiapoptosis: induction of TRAF1 and TRAF2 and c-IAP1 and c-IAP2 to suppress caspase-8 activation. , 1998, Science.

[14]  M. Su,et al.  Interferon‐γ expression by Th1 effector T cells mediated by the p38 MAP kinase signaling pathway , 1998, The EMBO journal.

[15]  M. Kaplan,et al.  Stat Proteins Control Lymphocyte Proliferation by Regulating p27Kip1 Expression , 1998, Molecular and Cellular Biology.

[16]  B. Groner,et al.  Phosphatidylinositol 3-kinase couples the interleukin-2 receptor to the cell cycle regulator E2F. , 1997, Immunity.

[17]  D. Cantrell,et al.  STAT3 Is a Serine Kinase Target in T Lymphocytes , 1997, The Journal of Biological Chemistry.

[18]  M. Malim,et al.  Suppression of tumor necrosis factor-induced cell death by inhibitor of apoptosis c-IAP2 is under NF-kappaB control. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[19]  P. Tsichlis,et al.  Transduction of interleukin-2 antiapoptotic and proliferative signals via Akt protein kinase. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[20]  R. Rees,et al.  Activation of STAT4 by IL-12 and IFN-alpha: evidence for the involvement of ligand-induced tyrosine and serine phosphorylation. , 1996, Journal of immunology.

[21]  M. Kaplan,et al.  Impaired IL-12 responses and enhanced development of Th2 cells in Stat4-deficient mice , 1996, Nature.

[22]  D. Carvajal,et al.  IL-12-Deficient Mice Are Defective in IFNγ Production and Type 1 Cytokine Responses , 1996 .

[23]  T. Idziorek,et al.  T helper type 1/T helper type 2 cytokines and T cell death: preventive effect of interleukin 12 on activation-induced and CD95 (FAS/APO-1)- mediated apoptosis of CD4+ T cells from human immunodeficiency virus- infected persons , 1995, The Journal of experimental medicine.

[24]  S. Szabo,et al.  Interleukin 12 signaling in T helper type 1 (Th1) cells involves tyrosine phosphorylation of signal transducer and activator of transcription (Stat)3 and Stat4 , 1995, The Journal of experimental medicine.

[25]  M. Colombo,et al.  IL-12 inhibits apoptosis induced in a human Th1 clone by gp120/CD4 cross-linking and CD3/TCR activation or by IL-2 deprivation. , 1995, Cellular immunology.

[26]  R. Rees,et al.  Interleukin 12 (IL-12) induces tyrosine phosphorylation of JAK2 and TYK2: differential use of Janus family tyrosine kinases by IL-2 and IL- 12 , 1995, The Journal of experimental medicine.

[27]  James M. Roberts,et al.  lnterleukin-2-mediated elimination of the p27Kipl cyclin-dependent kinase inhibitor prevented by rapamycin , 1994, Nature.

[28]  J. Roberts,et al.  Inactivation of a Cdk2 inhibitor during interleukin 2-induced proliferation of human T lymphocytes , 1994, Molecular and cellular biology.

[29]  K Y Hui,et al.  A specific inhibitor of phosphatidylinositol 3-kinase, 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002). , 1994, The Journal of biological chemistry.

[30]  R. Hewick,et al.  Cloning of cDNA for natural killer cell stimulatory factor, a heterodimeric cytokine with multiple biologic effects on T and natural killer cells. , 1991, Journal of immunology.

[31]  S. Clark,et al.  Identification and purification of natural killer cell stimulatory factor (NKSF), a cytokine with multiple biologic effects on human lymphocytes , 1989, The Journal of experimental medicine.

[32]  C. Thompson,et al.  The central effectors of cell death in the immune system. , 1999, Annual review of immunology.

[33]  R. Siegel,et al.  Mature T lymphocyte apoptosis--immune regulation in a dynamic and unpredictable antigenic environment. , 1999, Annual review of immunology.

[34]  L Adorini,et al.  The interleukin-12/interleukin-12-receptor system: role in normal and pathologic immune responses. , 1998, Annual review of immunology.

[35]  Andreas Radbruch,et al.  High gradient magnetic cell separation with MACS. , 1990, Cytometry.