Skip to main content
NCBI home page
Annals of the Rheumatic Diseases logoLink to Annals of the Rheumatic Diseases
. 2004 Nov;63(Suppl 2):ii67–ii71. doi: 10.1136/ard.2004.028290

Targeting the Jak/STAT pathway for immunosuppression

J O'Shea
PMCID: PMC1766780  PMID: 15479876

Full Text

The Full Text of this article is available as a PDF (180.4 KB).

Figure 1.

Figure 1

Open in a new tab

 Role of Janus kinases (Jaks) and signal transducers and activators of transcription (STATs) in cytokine signalling. Type I and Type II cytokine receptors associate with Jaks. Cytokine binding activates the Jaks, which phosphorylate the receptors allowing the recruitment of STATs. STATs are phosphorylated and accumulate in the nucleus where they regulate gene expression.

Figure 2.

Figure 2

Open in a new tab

 Cytokine signalling and the pathogenesis of severe combined immunodeficiency (SCID). Cytokines that use γc, interleukin (IL)-2, 4, 7, 9, 15, and 21, are essential for many aspects of immune cell development and function (see table 1). Mutations of IL-7R, γc, and Janus kinase3 (Jak)3 disrupt the action of these cytokines and lead to SCID. Mutations of these genes account for roughly two thirds to three quarters of the cases of SCID. X-SCID, X-linked SCID, AR-SCID, autosomal recessive SCID.

Figure 3.

Figure 3

Open in a new tab

 A selective Jak3 antagonist inhibits Janus kinase (Jak) activity, blocking early cytokine signalling and resultant signal transducer and activator of transcription (STAT) activation. The drug, CP-690 550, abrogates cytokine dependent gene regulation and subsequent lymphocyte activation. In this manner it blocks transplant rejection. STATs also have critical functions in mediating cytokine signalling and in principle, targeting STATs would also be useful to generate novel immunosuppressants.

Figure 4.

Figure 4

Open in a new tab

 Negative regulation of cytokine signalling. Cytokine signalling is attenuated by tyrosine phosphatases (PTPases), which dephosphorylate Janus kinases (Jaks), cytokine receptors and signal transducers and activators of transcription (STATs); several PTPases have been implicated in these functions. In addition, a family of protein inhibitors of STATs (PIAS) has also been shown to antagonise the action of these transcription factors. Finally, a family of cytokine inducible regulators of the Jak-STAT pathway, suppressors of cytokine signalling (SOCS proteins) has also been identified. In principle, activators, inducers, or mimics of the negative regulators of cytokine might also be useful as novel immunosuppressants.

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Agnello Davide, Lankford Carla S. R., Bream Jay, Morinobu Akio, Gadina Massimo, O'Shea John J., Frucht David M. Cytokines and transcription factors that regulate T helper cell differentiation: new players and new insights. J Clin Immunol. 2003 May;23(3):147–161. doi: 10.1023/a:1023381027062. [DOI] [PubMed] [Google Scholar]
  2. Asao H., Okuyama C., Kumaki S., Ishii N., Tsuchiya S., Foster D., Sugamura K. Cutting edge: the common gamma-chain is an indispensable subunit of the IL-21 receptor complex. J Immunol. 2001 Jul 1;167(1):1–5. doi: 10.4049/jimmunol.167.1.1. [DOI] [PubMed] [Google Scholar]
  3. Becker Todd C., Wherry E. John, Boone David, Murali-Krishna Kaja, Antia Rustom, Ma Averil, Ahmed Rafi. Interleukin 15 is required for proliferative renewal of virus-specific memory CD8 T cells. J Exp Med. 2002 Jun 17;195(12):1541–1548. doi: 10.1084/jem.20020369. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Boulay Jean-Louis, O'Shea John J., Paul William E. Molecular phylogeny within type I cytokines and their cognate receptors. Immunity. 2003 Aug;19(2):159–163. doi: 10.1016/s1074-7613(03)00211-5. [DOI] [PubMed] [Google Scholar]
  5. Boussiotis V. A., Barber D. L., Nakarai T., Freeman G. J., Gribben J. G., Bernstein G. M., D'Andrea A. D., Ritz J., Nadler L. M. Prevention of T cell anergy by signaling through the gamma c chain of the IL-2 receptor. Science. 1994 Nov 11;266(5187):1039–1042. doi: 10.1126/science.7973657. [DOI] [PubMed] [Google Scholar]
  6. Buckley R. H. Advances in the understanding and treatment of human severe combined immunodeficiency. Immunol Res. 2000;22(2-3):237–251. doi: 10.1385/IR:22:2-3:237. [DOI] [PubMed] [Google Scholar]
  7. Buckley R. H. Primary immunodeficiency diseases due to defects in lymphocytes. N Engl J Med. 2000 Nov 2;343(18):1313–1324. doi: 10.1056/NEJM200011023431806. [DOI] [PubMed] [Google Scholar]
  8. Buckley R. H., Schiff R. I., Schiff S. E., Markert M. L., Williams L. W., Harville T. O., Roberts J. L., Puck J. M. Human severe combined immunodeficiency: genetic, phenotypic, and functional diversity in one hundred eight infants. J Pediatr. 1997 Mar;130(3):378–387. doi: 10.1016/s0022-3476(97)70199-9. [DOI] [PubMed] [Google Scholar]
  9. Candotti F., Oakes S. A., Johnston J. A., Giliani S., Schumacher R. F., Mella P., Fiorini M., Ugazio A. G., Badolato R., Notarangelo L. D. Structural and functional basis for JAK3-deficient severe combined immunodeficiency. Blood. 1997 Nov 15;90(10):3996–4003. [PubMed] [Google Scholar]
  10. Candotti Fabio, Notarangelo Luigi, Visconti Roberta, O'Shea John. Molecular aspects of primary immunodeficiencies: lessons from cytokine and other signaling pathways. J Clin Invest. 2002 May;109(10):1261–1269. doi: 10.1172/JCI15769. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Candéias S., Peschon J. J., Muegge K., Durum S. K. Defective T-cell receptor gamma gene rearrangement in interleukin-7 receptor knockout mice. Immunol Lett. 1997 Jun 1;57(1-3):9–14. doi: 10.1016/s0165-2478(97)00062-x. [DOI] [PubMed] [Google Scholar]
  12. Changelian Paul S., Flanagan Mark E., Ball Douglas J., Kent Craig R., Magnuson Kelly S., Martin William H., Rizzuti Bonnie J., Sawyer Perry S., Perry Bret D., Brissette William H. Prevention of organ allograft rejection by a specific Janus kinase 3 inhibitor. Science. 2003 Oct 31;302(5646):875–878. doi: 10.1126/science.1087061. [DOI] [PubMed] [Google Scholar]
  13. Cooper Megan A., Bush Jennifer E., Fehniger Todd A., VanDeusen Jeffrey B., Waite Ross E., Liu Yang, Aguila Hector L., Caligiuri Michael A. In vivo evidence for a dependence on interleukin 15 for survival of natural killer cells. Blood. 2002 Jul 5;100(10):3633–3638. doi: 10.1182/blood-2001-12-0293. [DOI] [PubMed] [Google Scholar]
  14. Darnell J. E., Jr, Kerr I. M., Stark G. R. Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. Science. 1994 Jun 3;264(5164):1415–1421. doi: 10.1126/science.8197455. [DOI] [PubMed] [Google Scholar]
  15. Darnell James E., Jr Transcription factors as targets for cancer therapy. Nat Rev Cancer. 2002 Oct;2(10):740–749. doi: 10.1038/nrc906. [DOI] [PubMed] [Google Scholar]
  16. Druker Brian J. STI571 (Gleevec) as a paradigm for cancer therapy. Trends Mol Med. 2002;8(4 Suppl):S14–S18. doi: 10.1016/s1471-4914(02)02305-5. [DOI] [PubMed] [Google Scholar]
  17. Fehniger Todd A., Cooper Megan A., Caligiuri Michael A. Interleukin-2 and interleukin-15: immunotherapy for cancer. Cytokine Growth Factor Rev. 2002 Apr;13(2):169–183. doi: 10.1016/s1359-6101(01)00021-1. [DOI] [PubMed] [Google Scholar]
  18. Feldmann M., Maini R. N. Anti-TNF alpha therapy of rheumatoid arthritis: what have we learned? Annu Rev Immunol. 2001;19:163–196. doi: 10.1146/annurev.immunol.19.1.163. [DOI] [PubMed] [Google Scholar]
  19. Fry T. J., Mackall C. L. Interleukin-7: master regulator of peripheral T-cell homeostasis? Trends Immunol. 2001 Oct;22(10):564–571. doi: 10.1016/s1471-4906(01)02028-2. [DOI] [PubMed] [Google Scholar]
  20. Fry Terry J., Mackall Crystal L. Interleukin-7: from bench to clinic. Blood. 2002 Jun 1;99(11):3892–3904. doi: 10.1182/blood.v99.11.3892. [DOI] [PubMed] [Google Scholar]
  21. Glimcher L. H. Lineage commitment in lymphocytes: controlling the immune response. J Clin Invest. 2001 Oct;108(7):s25–s30. [PubMed] [Google Scholar]
  22. Goldrath Ananda W., Sivakumar Pallavur V., Glaccum Moira, Kennedy Mary K., Bevan Michael J., Benoist Christophe, Mathis Diane, Butz Eric A. Cytokine requirements for acute and Basal homeostatic proliferation of naive and memory CD8+ T cells. J Exp Med. 2002 Jun 17;195(12):1515–1522. doi: 10.1084/jem.20020033. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Ihle J. N. The Janus protein tyrosine kinase family and its role in cytokine signaling. Adv Immunol. 1995;60:1–35. doi: 10.1016/s0065-2776(08)60582-9. [DOI] [PubMed] [Google Scholar]
  24. Johnston J. A., Kawamura M., Kirken R. A., Chen Y. Q., Blake T. B., Shibuya K., Ortaldo J. R., McVicar D. W., O'Shea J. J. Phosphorylation and activation of the Jak-3 Janus kinase in response to interleukin-2. Nature. 1994 Jul 14;370(6485):151–153. doi: 10.1038/370151a0. [DOI] [PubMed] [Google Scholar]
  25. Karaghiosoff M., Neubauer H., Lassnig C., Kovarik P., Schindler H., Pircher H., McCoy B., Bogdan C., Decker T., Brem G. Partial impairment of cytokine responses in Tyk2-deficient mice. Immunity. 2000 Oct;13(4):549–560. doi: 10.1016/s1074-7613(00)00054-6. [DOI] [PubMed] [Google Scholar]
  26. Kawamura M., McVicar D. W., Johnston J. A., Blake T. B., Chen Y. Q., Lal B. K., Lloyd A. R., Kelvin D. J., Staples J. E., Ortaldo J. R. Molecular cloning of L-JAK, a Janus family protein-tyrosine kinase expressed in natural killer cells and activated leukocytes. Proc Natl Acad Sci U S A. 1994 Jul 5;91(14):6374–6378. doi: 10.1073/pnas.91.14.6374. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Leonard W. J., Noguchi M., Russell S. M., McBride O. W. The molecular basis of X-linked severe combined immunodeficiency: the role of the interleukin-2 receptor gamma chain as a common gamma chain, gamma c. Immunol Rev. 1994 Apr;138:61–86. doi: 10.1111/j.1600-065x.1994.tb00847.x. [DOI] [PubMed] [Google Scholar]
  28. Leonard W. J., O'Shea J. J. Jaks and STATs: biological implications. Annu Rev Immunol. 1998;16:293–322. doi: 10.1146/annurev.immunol.16.1.293. [DOI] [PubMed] [Google Scholar]
  29. Macchi P., Villa A., Giliani S., Sacco M. G., Frattini A., Porta F., Ugazio A. G., Johnston J. A., Candotti F., O'Shea J. J. Mutations of Jak-3 gene in patients with autosomal severe combined immune deficiency (SCID). Nature. 1995 Sep 7;377(6544):65–68. doi: 10.1038/377065a0. [DOI] [PubMed] [Google Scholar]
  30. Maraskovsky E., Teepe M., Morrissey P. J., Braddy S., Miller R. E., Lynch D. H., Peschon J. J. Impaired survival and proliferation in IL-7 receptor-deficient peripheral T cells. J Immunol. 1996 Dec 15;157(12):5315–5323. [PubMed] [Google Scholar]
  31. McMillan Sarah J., Bishop Benjamin, Townsend Michael J., McKenzie Andrew N., Lloyd Clare M. The absence of interleukin 9 does not affect the development of allergen-induced pulmonary inflammation nor airway hyperreactivity. J Exp Med. 2002 Jan 7;195(1):51–57. doi: 10.1084/jem.20011732. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Mella P., Schumacher R. F., Cranston T., de Saint Basile G., Savoldi G., Notarangelo L. D. Eleven novel JAK3 mutations in patients with severe combined immunodeficiency-including the first patients with mutations in the kinase domain. Hum Mutat. 2001 Oct;18(4):355–356. doi: 10.1002/humu.1199. [DOI] [PubMed] [Google Scholar]
  33. Migone T. S., Lin J. X., Cereseto A., Mulloy J. C., O'Shea J. J., Franchini G., Leonard W. J. Constitutively activated Jak-STAT pathway in T cells transformed with HTLV-I. Science. 1995 Jul 7;269(5220):79–81. doi: 10.1126/science.7604283. [DOI] [PubMed] [Google Scholar]
  34. Miyazaki T., Kawahara A., Fujii H., Nakagawa Y., Minami Y., Liu Z. J., Oishi I., Silvennoinen O., Witthuhn B. A., Ihle J. N. Functional activation of Jak1 and Jak3 by selective association with IL-2 receptor subunits. Science. 1994 Nov 11;266(5187):1045–1047. doi: 10.1126/science.7973659. [DOI] [PubMed] [Google Scholar]
  35. Murphy Kenneth M., Reiner Steven L. The lineage decisions of helper T cells. Nat Rev Immunol. 2002 Dec;2(12):933–944. doi: 10.1038/nri954. [DOI] [PubMed] [Google Scholar]
  36. Nelson Brad H. Interleukin-2 signaling and the maintenance of self-tolerance. Curr Dir Autoimmun. 2002;5:92–112. doi: 10.1159/000060549. [DOI] [PubMed] [Google Scholar]
  37. Noguchi M., Yi H., Rosenblatt H. M., Filipovich A. H., Adelstein S., Modi W. S., McBride O. W., Leonard W. J. Interleukin-2 receptor gamma chain mutation results in X-linked severe combined immunodeficiency in humans. Cell. 1993 Apr 9;73(1):147–157. doi: 10.1016/0092-8674(93)90167-o. [DOI] [PubMed] [Google Scholar]
  38. Notarangelo L. D., Giliani S., Mazza C., Mella P., Savoldi G., Rodriguez-Pérez C., Mazzolari E., Fiorini M., Duse M., Plebani A. Of genes and phenotypes: the immunological and molecular spectrum of combined immune deficiency. Defects of the gamma(c)-JAK3 signaling pathway as a model. Immunol Rev. 2000 Dec;178:39–48. doi: 10.1034/j.1600-065x.2000.17812.x. [DOI] [PubMed] [Google Scholar]
  39. Notarangelo L. D., Mella P., Jones A., de Saint Basile G., Savoldi G., Cranston T., Vihinen M., Schumacher R. F. Mutations in severe combined immune deficiency (SCID) due to JAK3 deficiency. Hum Mutat. 2001 Oct;18(4):255–263. doi: 10.1002/humu.1188. [DOI] [PubMed] [Google Scholar]
  40. O'Shea J. J. Jaks, STATs, cytokine signal transduction, and immunoregulation: are we there yet? Immunity. 1997 Jul;7(1):1–11. doi: 10.1016/s1074-7613(00)80505-1. [DOI] [PubMed] [Google Scholar]
  41. O'Shea John J., Gadina Massimo, Schreiber Robert D. Cytokine signaling in 2002: new surprises in the Jak/Stat pathway. Cell. 2002 Apr;109 (Suppl):S121–S131. doi: 10.1016/s0092-8674(02)00701-8. [DOI] [PubMed] [Google Scholar]
  42. Ortmann R., Smeltz R., Yap G., Sher A., Shevach E. M. A heritable defect in IL-12 signaling in B10.Q/J mice. I. In vitro analysis. J Immunol. 2001 May 1;166(9):5712–5719. doi: 10.4049/jimmunol.166.9.5712. [DOI] [PubMed] [Google Scholar]
  43. Ozaki Katsutoshi, Spolski Rosanne, Feng Carl G., Qi Chen-Feng, Cheng Jun, Sher Alan, Morse Herbert C., 3rd, Liu Chengyu, Schwartzberg Pamela L., Leonard Warren J. A critical role for IL-21 in regulating immunoglobulin production. Science. 2002 Nov 22;298(5598):1630–1634. doi: 10.1126/science.1077002. [DOI] [PubMed] [Google Scholar]
  44. Parganas E., Wang D., Stravopodis D., Topham D. J., Marine J. C., Teglund S., Vanin E. F., Bodner S., Colamonici O. R., van Deursen J. M. Jak2 is essential for signaling through a variety of cytokine receptors. Cell. 1998 May 1;93(3):385–395. doi: 10.1016/s0092-8674(00)81167-8. [DOI] [PubMed] [Google Scholar]
  45. Parham Christi, Chirica Madaline, Timans Jacqueline, Vaisberg Elena, Travis Marilyn, Cheung Jeanne, Pflanz Stefan, Zhang Rebecca, Singh Komal P., Vega Felix. A receptor for the heterodimeric cytokine IL-23 is composed of IL-12Rbeta1 and a novel cytokine receptor subunit, IL-23R. J Immunol. 2002 Jun 1;168(11):5699–5708. doi: 10.4049/jimmunol.168.11.5699. [DOI] [PubMed] [Google Scholar]
  46. Peschon J. J., Morrissey P. J., Grabstein K. H., Ramsdell F. J., Maraskovsky E., Gliniak B. C., Park L. S., Ziegler S. F., Williams D. E., Ware C. B. Early lymphocyte expansion is severely impaired in interleukin 7 receptor-deficient mice. J Exp Med. 1994 Nov 1;180(5):1955–1960. doi: 10.1084/jem.180.5.1955. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Puel A., Ziegler S. F., Buckley R. H., Leonard W. J. Defective IL7R expression in T(-)B(+)NK(+) severe combined immunodeficiency. Nat Genet. 1998 Dec;20(4):394–397. doi: 10.1038/3877. [DOI] [PubMed] [Google Scholar]
  48. Roberts Joseph L., Lengi Andrea, Brown Stephanie M., Chen Min, Zhou Yong-Jie, O'Shea John J., Buckley Rebecca H. Janus kinase 3 (JAK3) deficiency: clinical, immunologic, and molecular analyses of 10 patients and outcomes of stem cell transplantation. Blood. 2003 Nov 13;103(6):2009–2018. doi: 10.1182/blood-2003-06-2104. [DOI] [PubMed] [Google Scholar]
  49. Rodig S. J., Meraz M. A., White J. M., Lampe P. A., Riley J. K., Arthur C. D., King K. L., Sheehan K. C., Yin L., Pennica D. Disruption of the Jak1 gene demonstrates obligatory and nonredundant roles of the Jaks in cytokine-induced biologic responses. Cell. 1998 May 1;93(3):373–383. doi: 10.1016/s0092-8674(00)81166-6. [DOI] [PubMed] [Google Scholar]
  50. Russell S. M., Johnston J. A., Noguchi M., Kawamura M., Bacon C. M., Friedmann M., Berg M., McVicar D. W., Witthuhn B. A., Silvennoinen O. Interaction of IL-2R beta and gamma c chains with Jak1 and Jak3: implications for XSCID and XCID. Science. 1994 Nov 11;266(5187):1042–1045. doi: 10.1126/science.7973658. [DOI] [PubMed] [Google Scholar]
  51. Schluns K. S., Kieper W. C., Jameson S. C., Lefrançois L. Interleukin-7 mediates the homeostasis of naïve and memory CD8 T cells in vivo. Nat Immunol. 2000 Nov;1(5):426–432. doi: 10.1038/80868. [DOI] [PubMed] [Google Scholar]
  52. Schluns Kimberly S., Williams Kristina, Ma Averil, Zheng Xin X., Lefrançois Leo. Cutting edge: requirement for IL-15 in the generation of primary and memory antigen-specific CD8 T cells. J Immunol. 2002 May 15;168(10):4827–4831. doi: 10.4049/jimmunol.168.10.4827. [DOI] [PubMed] [Google Scholar]
  53. Seddon Benedict, Tomlinson Peter, Zamoyska Rose. Interleukin 7 and T cell receptor signals regulate homeostasis of CD4 memory cells. Nat Immunol. 2003 Jun 15;4(7):680–686. doi: 10.1038/ni946. [DOI] [PubMed] [Google Scholar]
  54. Shaw Michael H., Boyartchuk Victor, Wong Sandy, Karaghiosoff Marina, Ragimbeau Josiane, Pellegrini Sandra, Muller Mathias, Dietrich William F., Yap George S. A natural mutation in the Tyk2 pseudokinase domain underlies altered susceptibility of B10.Q/J mice to infection and autoimmunity. Proc Natl Acad Sci U S A. 2003 Sep 18;100(20):11594–11599. doi: 10.1073/pnas.1930781100. [DOI] [PMC free article] [PubMed] [Google Scholar]
  55. Shimoda K., Kato K., Aoki K., Matsuda T., Miyamoto A., Shibamori M., Yamashita M., Numata A., Takase K., Kobayashi S. Tyk2 plays a restricted role in IFN alpha signaling, although it is required for IL-12-mediated T cell function. Immunity. 2000 Oct;13(4):561–571. doi: 10.1016/s1074-7613(00)00055-8. [DOI] [PubMed] [Google Scholar]
  56. Temann Ulla-Angela, Ray Prabir, Flavell Richard A. Pulmonary overexpression of IL-9 induces Th2 cytokine expression, leading to immune pathology. J Clin Invest. 2002 Jan;109(1):29–39. doi: 10.1172/JCI13696. [DOI] [PMC free article] [PubMed] [Google Scholar]
  57. Townsend J. M., Fallon G. P., Matthews J. D., Smith P., Jolin E. H., McKenzie N. A. IL-9-deficient mice establish fundamental roles for IL-9 in pulmonary mastocytosis and goblet cell hyperplasia but not T cell development. Immunity. 2000 Oct;13(4):573–583. doi: 10.1016/s1074-7613(00)00056-x. [DOI] [PubMed] [Google Scholar]
  58. Trinchieri Giorgio, Pflanz Stefan, Kastelein Robert A. The IL-12 family of heterodimeric cytokines: new players in the regulation of T cell responses. Immunity. 2003 Nov;19(5):641–644. doi: 10.1016/s1074-7613(03)00296-6. [DOI] [PubMed] [Google Scholar]
  59. Turkson James, Kim Joon S., Zhang Shumin, Yuan Jing, Huang Mei, Glenn Matthew, Haura Eric, Sebti Said, Hamilton Andrew D., Jove Richard. Novel peptidomimetic inhibitors of signal transducer and activator of transcription 3 dimerization and biological activity. Mol Cancer Ther. 2004 Mar;3(3):261–269. [PubMed] [Google Scholar]
  60. Velazquez L., Fellous M., Stark G. R., Pellegrini S. A protein tyrosine kinase in the interferon alpha/beta signaling pathway. Cell. 1992 Jul 24;70(2):313–322. doi: 10.1016/0092-8674(92)90105-l. [DOI] [PubMed] [Google Scholar]
  61. Vollmer Timothy, Key Lyndon, Durkalski Valerie, Tyor William, Corboy John, Markovic-Plese Silva, Preiningerova Jana, Rizzo Marco, Singh Inderjit. Oral simvastatin treatment in relapsing-remitting multiple sclerosis. Lancet. 2004 May 15;363(9421):1607–1608. doi: 10.1016/S0140-6736(04)16205-3. [DOI] [PubMed] [Google Scholar]
  62. Waldmann T. A., O'Shea J. The use of antibodies against the IL-2 receptor in transplantation. Curr Opin Immunol. 1998 Oct;10(5):507–512. doi: 10.1016/s0952-7915(98)80215-x. [DOI] [PubMed] [Google Scholar]
  63. Witthuhn B. A., Silvennoinen O., Miura O., Lai K. S., Cwik C., Liu E. T., Ihle J. N. Involvement of the Jak-3 Janus kinase in signalling by interleukins 2 and 4 in lymphoid and myeloid cells. Nature. 1994 Jul 14;370(6485):153–157. doi: 10.1038/370153a0. [DOI] [PubMed] [Google Scholar]
  64. Wormald Samuel, Hilton Douglas J. Inhibitors of cytokine signal transduction. J Biol Chem. 2003 Nov 7;279(2):821–824. doi: 10.1074/jbc.R300030200. [DOI] [PubMed] [Google Scholar]
  65. Wurster A. L., Tanaka T., Grusby M. J. The biology of Stat4 and Stat6. Oncogene. 2000 May 15;19(21):2577–2584. doi: 10.1038/sj.onc.1203485. [DOI] [PubMed] [Google Scholar]
  66. Youssef Sawsan, Stüve Olaf, Patarroyo Juan C., Ruiz Pedro J., Radosevich Jennifer L., Hur Eun Mi, Bravo Manuel, Mitchell Dennis J., Sobel Raymond A., Steinman Lawrence. The HMG-CoA reductase inhibitor, atorvastatin, promotes a Th2 bias and reverses paralysis in central nervous system autoimmune disease. Nature. 2002 Nov 7;420(6911):78–84. doi: 10.1038/nature01158. [DOI] [PubMed] [Google Scholar]
  67. Yu Hua, Jove Richard. The STATs of cancer--new molecular targets come of age. Nat Rev Cancer. 2004 Feb;4(2):97–105. doi: 10.1038/nrc1275. [DOI] [PubMed] [Google Scholar]

Articles from Annals of the Rheumatic Diseases are provided here courtesy of BMJ Publishing Group

RESOURCES