%0 Journal Article
%T Inhibitory effects of the JAK inhibitor CP690,550 on human CD4+ T lymphocyte cytokine production
%A Kiyoshi Migita
%A Taiichiro Miyashita
%A Yasumori Izumi
%A Tomohiro Koga
%A Atsumasa Komori
%A Yumi Maeda
%A Yuka Jiuchi
%A Yoshihiro Aiba
%A Satoshi Yamasaki
%A Atsushi Kawakami
%A Minoru Nakamura
%A Hiromi Ishibashi
%J BMC Immunology
%D 2011
%I BioMed Central
%R 10.1186/1471-2172-12-51
%X CD4+ T cells produced IL-2, IL-4, IL-17, IL-22 and IFN-¦Ã 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-¦Ã 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.Therefore, CP690,550-mediated modification of the JAK/STAT pathway may be a new immunosuppressive strategy in the treatment of autoimmune diseases.Janus kinases (JAKs) are cytoplasmic tyrosine kinases that participate in the signaling of cell surface receptors, particularly cytokine receptors [1]. Ligand-cytokine receptor binding induces activation of JAKs, which initiate signaling by phosphorylating cytokine receptors and creating docking sites for signaling proteins, known as signal transducers and activators of transcription (STATs) [2]. JAKs catalyze STAT phosphorylation to facilitate STAT dimerization, transport to the nucleus and ultimately regulate gene expression [3]. Of the members of the JAK family, JAK3 has features that make it a potentially attractive target for immunosuppression, since JAK3 associates with the common gamma (c¦Ã) chain, which is shared by receptors of IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21 [4]. Moreover, mice and humans with a heritable absence or mutation of JAK3 express a severe combined immunodeficiency phenotype [5,6]. Therefore selective inhibition of JAK3 represents an optimal strategy for immunosuppression and the treatment of autoimmune diseases [7]. CP690,550, a JAK3 inhibitor that is currently in clinical trials, has been shown to significantly reduce joint inflammation in rheumatoid arthritis (RA) [8,9]. The JAK/STAT pathways influence cell-fate decisions made by differentiating na£¿ve T cells, helping to control their development into Th1 Th2 and Th17 cells [10]. Commitment
%K CP690
%K 550
%K cytokines
%K Janus kinase
%K signal transducers and activators of transcription
%K T lymphocytes
%U http://www.biomedcentral.com/1471-2172/12/51