Inhibitory effects of the JAK inhibitor CP690,550 on human CD4+ T lymphocyte cytokine production

BMC Immunology

Hiromi Ishibashi¹  Minoru Nakamura¹  Atsushi Kawakami²  Satoshi Yamasaki²  Yoshihiro Aiba¹  Yuka Jiuchi¹  Yumi Maeda¹  Atsumasa Komori¹  Tomohiro Koga¹  Yasumori Izumi¹  Taiichiro Miyashita¹  Kiyoshi Migita¹ 

[1] Department of Rheumatology and Clinical Research Center, NHO Nagasaki Medical Center, Kubara 2-1001-1, Omura 856-8652, Japan;Department of Rheumatology, Nagasaki University Hospital, Sakamoto 1-7-1 Nagasaki 852-8501, Japan

关键词: T lymphocytes;    signal transducers and activators of transcription;    Janus kinase;    cytokines;    550;    CP690;   

Others  :  1077985
DOI  :  10.1186/1471-2172-12-51

 received in 2011-01-21, accepted in 2011-08-31,  发布年份 2011

【 摘 要 】

Background

The new JAK3 inhibitor, CP690,550, has shown efficacy in the treatment of rheumatoid arthritis. The present study was undertaken to assess the effects of CP690,550 on cytokine production and cellular signaling in human CD4⁺ T cells.

Results

CD4⁺ T cells produced IL-2, IL-4, IL-17, IL-22 and IFN-γ in following stimulation with a CD3 antibody. At the optimal concentration, CP690,550 almost completely inhibited the production of IL-4, IL-17, IL-22 and IFN-γ from these activated CD4⁺ T cells, but only had marginal effects on IL-2 production. Moreover CP690,550 inhibited anti-CD3-induced phosphorylation of STAT1, STAT3, STAT4, STAT5, and STAT6, but not the TCR-associated phosphorylation of ZAP-70.

Conclusions

Therefore, CP690,550-mediated modification of the JAK/STAT pathway may be a new immunosuppressive strategy in the treatment of autoimmune diseases.

【 授权许可】

   
2011 Migita et al; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

Figure 5.

Figure 6.

Figure 7.

Figure 8.

【 参考文献 】

• [1]Schindler C, Levy DE, Decker T: JAK-STAT signaling: from interferons to cytokines. J Biol Chem 2007, 282:20059-63.
• [2]Leonard WJ, O'Shea JJ: Jaks and STATs: biological implications. Annu Rev Immunol 1998, 16:293-322.
• [3]Levy DE, Darnell JE Jr: Stats: transcriptional control and biological impact. Nat Rev Mol Cell Biol 2002, 3:651-62.
• [4]O'Shea JJ, Pesu M, Borie DC, Changelian PS: A new modality for immunosuppression: targeting the JAK/STAT pathway. Nat Rev Drug Discov 2004, 3:555-64.
• [5]Noguchi M, Yi H, Rosenblatt HM, Filipovich AH, Adelstein S, Modi WS, McBride OW, Leonard WJ: Interleukin-2 receptor gamma chain mutation results in X-linked severe combined immunodeficiency in humans. Cell 1993, 73:147-57.
• [6]Nosaka T, van Deursen JM, Tripp RA, Thierfelder WE, Witthuhn BA, McMickle AP, Doherty PC, Grosveld GC, Ihle JN: Defective lymphoid development in mice lacking Jak3. Science 1995, 270:800-2.
• [7]Pesu M, Laurence A, Kishore N, Zwillich SH, Chan G, O'Shea JJ: Therapeutic targeting of Janus kinases. Immunol Rev 2008, 223:132-42.
• [8]Kremer JM, Bloom BJ, Breedveld FC, Coombs JH, Fletcher MP, Gruben D, Krishnaswami S, Burgos-Vargas R, Wilkinson B, Zerbini CA, Zwillich SH: The safety and efficacy of a JAK inhibitor in patients with active rheumatoid arthritis: Results of a double-blind, placebo-controlled phase IIa trial of three dosage levels of CP-690,550 versus placebo. Arthritis Rheum 2009, 60:1895-905.
• [9]Coombs JH, Bloom BJ, Breedveld FC, Fletcher MP, Gruben D, Kremer JM, Burgos-Vargas R, Wilkinson B, Zerbini CA, Zwillich SH: Improved pain, physical functioning and health status in patients with rheumatoid arthritis treated with CP-690,550, an orally active Janus kinase (JAK) inhibitor: results from a randomised, double-blind, placebo-controlled trial. Ann Rheum Dis 2010, 69:413-6.
• [10]Murphy KM, Reiner SL: The lineage decisions of helper T cells. Nat Rev Immunol 2002, 2:933-44.
• [11]Szabo SJ, Sullivan BM, Peng SL, Glimcher LH: Molecular mechanisms regulating Th1 immune responses. Annu Rev Immunol 2003, 21:713-58.
• [12]Paul WE: What determines Th2 differentiation, in vitro and in vivo? Immunol Cell Biol 2010, 88:236-9.
• [13]Chen Z, Laurence A, O'Shea JJ: Signal transduction pathways and transcriptional regulation in the control of Th17 differentiation. Semin Immunol 2007, 19:400-8.
• [14]Scheinecker C, Redlich K, Smolen JS: Cytokines as therapeutic targets: advances and limitations. Immunity 2008, 28:440-4.
• [15]Cohen S, Fleischmann R: Kinase inhibitors: a new approach to rheumatoid arthritis treatment. Curr Opin Rheumatol 2010, 22:330-5.
• [16]Murphy KM, Reiner SL: The lineage decisions of helper T cells. Nat Rev Immunol 2002, 2:933-44.
• [17]Zhu J, Yamane H, Paul WE: Differentiation of effector CD4 T cell populations. Annu Rev Immunol 2010, 28:445-89.
• [18]Seder RA, Paul WE: Acquisition of lymphokine-producing phenotype by CD4+ T cells. Annu Rev Immunol 1994, 12:635-73.
• [19]Zhou L, Chong MM, Littman DR: Plasticity of CD4+ T cell lineage differentiation. Immunity 2009, 30:646-55.
• [20]Leonard WJ: X-linked severe combined immunodeficiency: from molecular cause to gene therapy within seven years. Mol Med Today 2000, 6:403-7.
• [21]Murphy KM, Ouyang W, Szabo SJ, Jacobson NG, Guler ML, Gorham JD, Gubler U, Murphy TL: T helper differentiation proceeds through Stat1-dependent, Stat4-dependent and Stat4-independent phases. Curr Top Microbiol Immunol 1999, 238:13-26.
• [22]Imada K, Leonard WJ: The Jak-STAT pathway. Mol Immunol 2000, 37:1-11.
• [23]Cote-Sierra J, Foucras G, Guo L, Chiodetti L, Young HA, Hu-Li J, Zhu J, Paul WE: Interleukin 2 plays a central role in Th2 differentiation. Proc Natl Acad Sci USA 2004, 101:3880-5.
• [24]Changelian PS, Flanagan ME, Ball DJ, Kent CR, Magnuson KS, Martin WH, Rizzuti BJ, Sawyer PS, Perry BD, Brissette WH, McCurdy SP, Kudlacz EM, Conklyn MJ, Elliott EA, Koslov ER, Fisher MB, Strelevitz TJ, Yoon K, Whipple DA, Sun J, Munchhof MJ, Doty JL, Casavant JM, Blumenkopf TA, Hines M, Brown MF, Lillie BM, Subramanyam C, Shang-Poa C, Milici AJ, et al.: Prevention of organ allograft rejection by a specific Janus kinase 3 inhibitor. Science 2003, 302:875-8.
• [25]Williams NK, Bamert RS, Patel O, Wang C, Walden PM, Wilks AF, Fantino E, Rossjohn J, Lucet IS: Dissecting specificity in the Janus kinases: the structures of JAK-specific inhibitors complexed to the JAK1 and JAK2 protein tyrosine kinase domains. J Mol Biol 2009, 387:219-32.
• [26]Jiang JK, Ghoreschi K, Deflorian F, Chen Z, Perreira M, Pesu M, Smith J, Nguyen DT, Liu EH, Leister W, Costanzi S, O'Shea JJ, Thomas CJ: Examining the chirality, conformation and selective kinase inhibition of 3-((3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile (CP-690,550). J Med Chem 2008, 51:8012-8.
• [27]Shi M, Lin TH, Appell KC, Berg LJ: Janus-kinase-3-dependent signals induce chromatin remodeling at the Ifng locus during T helper 1 cell differentiation. Immunity 2008, 28:763-73.
• [28]Park H, Li Z, Yang XO, Nurieva R, Wang YH, Wang Y, Hood L, Zhu Z, Tian Q, Dong C: A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat Immunol 2005, 6:1133-41.
• [29]Annunziato F, Cosmi L, Liotta F, Maggi E, Romagnani S: Type 17 T helper cells-origins, features and possible roles in rheumatic disease. Nat Rev Rheumatol 2009, 5:325-31.
• [30]Aujla SJ, Kolls JK: IL-22: a critical mediator in mucosal host defense. J Mol Med 2009, 87:451-4.
• [31]Liu XK, Lin X, Gaffen SL: Crucial role for nuclear factor of activated T cells in T cell receptor-mediated regulation of human interleukin-17. J Biol Chem 2004, 279:52762-71.
• [32]Korn T, Bettelli E, Oukka M, Kuchroo VK: IL-17 and Th17 Cells. Annu Rev Immunol 2009, 27:485-517.
• [33]Liu X, Lee YS, Yu CR, Egwuagu CE: Loss of STAT3 in CD4+ T cells prevents development of experimental autoimmune diseases. J Immunol 2008, 180:6070-6.
• [34]Durant L, Watford WT, Ramos HL, Laurence A, Vahedi G, Wei L, Takahashi H, Sun HW, Kanno Y, Powrie F, O'Shea JJ: Diverse targets of the transcription factor STAT3 contribute to T cell pathogenicity and homeostasis. Immunity 2010, 32:605-15.
• [35]Berridge MJ: Lymphocyte activation in health and disease. Crit Rev Immunol 1997, 17:155-78.
• [36]Ghoreschi K, Laurence A, O'Shea JJ: Janus kinases in immune cell signaling. Immunol Rev 2009, 228:273-87.