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Review
. 2004 Nov;63 Suppl 2(Suppl 2):ii67-ii71.
doi: 10.1136/ard.2004.028290.

Targeting the Jak/STAT pathway for immunosuppression

J J O'shea  1
Affiliations
Review

Targeting the Jak/STAT pathway for immunosuppression

J J O'shea. Ann Rheum Dis. 2004 Nov.
No abstract available

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Figures

Figure 1
Figure 1
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
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
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
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.
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