Rationale For Selective Targeting Of Jak3 In Inflammatory Diseases

The JAK signal transducer and activator of transcription (STAT) signaling pathway has been extensively studied but specific details regarding cascade regulation remain unelucidated [6]. In cells, JAK3 associates with cytokine receptors, which homodimerize and heterodimerize upon binding of the ligand. JAK3 binds specifically to the gamma common chain (gc) that is shared by the cytokine receptors for interleukin-2 (IL-2), IL-4, IL-7, IL-9, IL-15 and IL-21 [5]. Upon ligand binding, JAK3 becomes activated in concert with JAK1 through transphosphorylation which in turn results in phosphorylation of the receptor. Receptor phosphoryla-tion then results in binding and phosphorylation of an associated STAT protein (e.g., STAT5 in the case of IL-2 stimulation and STAT6 in the case of IL-4 stimulation). After STAT dimerization, the complex is thought to translocate to the nucleus, interact with DNA, and initiate transcription of target genes (Figure 1).

Because JAK3 plays a specific role in regulating gc cytokine signaling and is primarily expressed in lymphoid tissues, it appears to be a selective regulator of lymphoid development and function within the immune system [7]. This is consistent with the SCID phenotype that has been identified in a subpopulation of patients that harbor abnormalities associated with JAK3 based on genetic analysis [8]. These abnormalities

pathway.

include a 'kinase dead' mutant, a mutant incapable of binding the gc of the IL-2 family of receptors, or a lack of detectable JAK3 protein, each of which is associated with a human SCID phenotype [9]. This disorder is characterized by a significant decrease in the number of circulating T and NK cells with normal numbers of B cells (albeit with compromised B-cell function). Hematopoetic stem cell transplantation results in the normalization of the T-cell population in these patients [10]. Since patients with defects in JAK3 show symptoms that are restricted to the immune system, it follows that a selective inhibitor of JAK3 could function as a well-tolerated immunosuppressant for use in a number of autoimmune disorders [11]. In comparison with JAK3, the other JAK family members, JAK1, JAK2 and TYK2, are known to be more ubiquitous in their expression patterns. In addition to participating in concert with JAK3 in the signaling of the IL-2 family of cytokine receptors, JAK1 has been shown to be a regulator of IL-6 and gp130 cytokine signaling. It has therefore been suggested that dual inhibition of JAK1 and JAK3 might lead to enhanced cellular potency and broader immunosuppressive effects, but may also increase the risk of viral and bacterial infections [12]. Moreover, JAK1 has been linked to tumor surveillance [13], and JAK1 knockout mice do not thrive, as the pups fail to nurse because of presumed neurological defects [14]. Despite these potential concerns, no adverse clinical outcome has been conclusively linked to JAK1 inhibition

(vide infra). These observations make it difficult to assess the risk to benefit ratio of dual inhibition of JAK1 and JAK3 a priori. JAK2 is classically associated with interferon-^ (IFN-g) production through the IL-12 pathway; however, it also mediates the signaling of important hematopoietic growth factors such as erythropoietin (EPO), thrombopoietin (TPO) and granulocyte macrophage colony-stimulating factor (GM-CSF). As a result, JAK2 inhibitors are being examined for oncological applications, and this is beyond the scope of this review. It has been suggested that JAK2 inhibition may result in adverse hematopoietic effects such as anemia, thrombocytopenia and generalized leukopenia in the clinic [12].

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