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Interleukins and Janus Kinases: Emerging Therapeutic Targets in Rheumatoid Arthritis
Rupal Mansukhani, PharmD
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Interleukins and Janus Kinases: Emerging Therapeutic Targets in Rheumatoid Arthritis

Rupal Mansukhani, PharmD
IL-1 Family
The IL-1 gene family consists of IL-1a, IL-1b, and IL-1Ra.12 RA disease activity and progression of joint destruction correlate with the plasma and synovial fluid levels of IL-1. IL-1 is produced in response to inflammatory stimuli and mediates various physiologic responses, including inflammatory and immunological responses. IL-1a and IL-1b are proinflammatory agonist molecules. IL-1a is primarily bound to the membrane, whereas IL-1b is predominantly extracellular. Two specific immunoglobulin-like membrane-bound IL-1 receptors (IL-1Rs), types I and II, are found in humans. IL-1R type I (IL-1RI) is expressed by T cells, endothelial cells, and fibroblasts; IL-1R type II (IL-1RII) is expressed primarily on B cells, monocytes, and neutrophils (and is not functionally active). Both receptors bind IL-1b with similar affinities. IL-R1II has a substantially lower binding affinity for IL-1a than does IL-1RI. A complete biological response requires about 2% occupancy of IL-R1I receptors on a target cell. Both types of receptors are produced naturally and compete for circulating IL-1a and IL-1b. IL-1Ra is the third member of the IL-1 family.12
IL-6 Family
IL-6 has pro- and anti-inflammatory properties.5 It is produced by B cells, T cells, fibroblasts, endothelial cells, monocytes, macrophages, keratinocytes, chondrocytes, and some tumor cells. Evidence suggests that, depending on the signaling (classic), IL-6 trans-signaling is a major factor in RA pathogenesis.9 A high level of IL-6 has been found in the blood and cerebrospinal fluid of many patients with RA.5
IL-17 Family
The IL-17 family of cytokines plays a key regulatory role in host defense and inflammatory diseases. Currently, 6 IL-17 family ligands have been identified (Table13). The biologic function and regulation of IL-17A and IL-17F are the best understood. The IL-17 cytokine family mediates its biologic functions via cell surface receptors. Five IL-17 receptors have been identified: IL-17RA, IL-17RB/IL-25R, IL-17RC, IL-17RD/SEF, and IL-17RE.13

Both IL-17 and IL-17F defend the host against certain pathogens.11 Their function is most apparent at epithelial and mucosal barriers, such as the lung, gut, and oral cavity. Mucosal surfaces, in particular, are rich with cells that produce IL-17. Moreover, Th17 cells express a receptor that enables them to target mucosal surfaces.11

With regard to defensive immunity, IL-17 induces and regulates the production of proinflammatory cytokines that mediate a variety of defensive responses.11 Some of these IL-17–induced cytokines demonstrate antimicrobial activity and are able to directly kill invading microorganisms, whereas others act to further amplify Th17 cell differentiation.11

In particular, IL-17 and IL-17F are vital for the clearance of extracellular bacteria, such as Staphylococcus aureus, Citrobacter rodentium, and Klebsiella pneumoniae, and the control of fungal infections, such as Pneumocystis carinii and Candida albicans.13 The protective activity of IL-17 is not limited to extracellular pathogens. IL-17 also defends against intracellular bacteria; however, the exact mechanisms by which it does so are not completely clear.11
Janus Kinases
Protein kinases are enzymes involved in intracellular signaling. They are capable of changing the function of proteins via phosphorylation.14 Numerous fundamental processes, such as cell growth and differentiation, are regulated by phosphorylation. Furthermore, several key immune receptors, including those that drive inflammation, exert their effects through protein kinases.14
From over 500 protein kinases that are currently known, 90 are protein tyrosine kinases, which are classified into 2 groups: receptor tyrosine kinases and nonreceptor tyrosine kinases.1,15 JAKs belong to the nonreceptor protein tyrosine kinase group and have been identified as potential inhibitory targets in RA. JAKs engage with many different cytokines, growth factors, and hormones, and mediate tyrosine phosphorylation of their associated receptors and recruited signaling proteins. JAKs exert their effect primarily through activation of specific signaling proteins known as signal transducers and activators of transcription (STATs).1,15 STATs can then modulate intracellular activity, including the expression of target genes. This leads to expression of proinflammatory cytokines, which activate other immune cells. There are 7 different STATs: STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, and STAT6, which pair up with 1 of 4 members of the JAK family of protein kinases. The 4 that have been identified are JAK1, JAK2, JAK3, and tyrosine kinase 2 (Tyk2). The cytokines known as interferon alpha, beta, and gamma, signal through the JAK-STAT pathway. This immune response can also stimulate tumor necrosis factor (TNF), IL-1, and IL-17.16

JAKs are critical components of many cytokine receptor systems regulating growth, survival, differentiation, and pathogen resistance.15 Functional JAK signaling is necessary for innate and adaptive immune responses that protect the organism from infections and immunodeficiencies. Conversely, activating mutations or loss-of-function mutations in JAK genes, which impair JAK signaling, leads to inflammatory disease, erythrocytosis, gigantism, and malignant transformation of lymphocytes or myeloid cells.15,17

Type I and II cytokine receptors are important to regulate immune-mediated diseases. Cytokines that bind to types I and II initiate the JAK-STAT pathway to block immune-mediated diseases.16 Numerous receptors use JAK1, JAK2, JAK3, and Tyk2 for intracellular signal transduction.14,18 JAK1 is involved in the signal transduction of many type I and type II cytokine receptors.19 Although some JAKs, such as JAK1, associate with multiple cytokine receptor subunits, JAK3 is unique in that it associates with only 1 receptor subunit: the common gamma chain.14,18 Several proinflammatory cytokines signal through the common gamma chain, including interferon gamma, IL-2, IL-4, IL-6, IL-7, IL-10, IL-12, and IL-15, all of which are associated with synovial inflammation.20 Thus, inhibiting the signaling of these cytokines may be a reasonable therapeutic target in RA. The synovial tissue of patients with RA expresses JAK3 and STAT.21 Successful disease-modifying antirheumatic drug (DMARD) treatment was found to reduce synovial expression of both JAK3 and STAT.

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