JAK3 has the most selective function; JAK3 is thought to associate uniquely with γ_c, the shared subunit of the cytokine receptors used by IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21. Inhibition of JAK3, therefore, blocks signalling by these cytokines. γ_c cytokines also utilize JAK1, so agents that inhibit JAK1 will also block signalling by these cytokines. In contrast to JAK3, JAK1 is also used by a number of other cytokines: those that signal via gp130; IFNs; and IL-10-family cytokines. Similar to JAK1, JAK2 is important for signalling by an array of cytokines including IFN-γ, IL-6, and other cytokines. JAK2 is important for signalling by IL-3, IL-5 and GM-CSF, and is essential for signalling by EPO, TPO and growth hormone. Therefore, inhibitors that block both JAK1 and JAK2 interfere not only with signalling by many proinflammatory cytokines, but also with EPO signalling and thus can cause anaemia. TYK2 also contributes to IL-6 and IL-10 signalling and is especially important for the actions of IFN-α and IFN-β. At present, there are no TYK2 inhibitors in clinical use. Abbreviations: βc, cytokine receptor common subunit β; EPO, erythropoietin; γ_c, cytokine receptor common subunit γ; GM-CSF, granulocyte-macrophage colony-stimulating factor; IFN, interferon; JAK, Janus kinase; jakinibs, JAK inhibitors; LIF, leukaemia inhibitory factor; OSM, oncostatin-M; TPO, thrombopoietin; TYK2, tyrosine kinase 2.

Of note, IL-1, IL-17 and TNF do not signal via the JAK–STAT pathway. Shown here are the signal transduction pathways stemming from the IL-2R in T cells, culminating in the activation of STAT5, MAPKs and mTOR. The Ras–Raf–MAPK pathway is linked to cytokine receptors by adapter molecules such as SHC, GRB2 and SOS. IL-2 and other cytokines also activate PDK1 and PKB (also known as AKT), leading to activation of mTOR. Although the term JAK–STAT pathway is frequently used, other pathways are also activated. These pathways also seems to be dependent on JAKs; however, this area deserves further research. Tyrosine and lipid kinases are indicated in red and serine/threonine kinases are indicated in blue. The effect of various jakinibs are listed, as are mTOR inhibitors. Abbreviations: AMPK, 5'-AMP-activated protein kinase; FKBP12, 12kDa FK506 binding protein; GRB2, growth factor receptor-bound protein 2; IL-2R, IL-2 receptor; JAK, Janus kinase; jakinibs, JAK inhibitors; MAPK, mitogen-activated protein kinase; mLST8, mammalian lethal with SEC13 protein 8; mTOR, mammalian target of rapamycin; PDK1, 3-phosphoinositide-dependent protein kinase 1; PI3K, phosphoinositide 3-kinase; PIP₃, phosphatidylinositol (3,4,5)-trisphosphate; PKB, protein kinase B; pY, phosphorylated tyrosine residues; Rheb, Ras homolog enriched in brain; SOS, son of sevenless; STAT, signal transducer and activator of transcription; TSC1, tuberous sclerosis 1 protein; TSC2, tuberous sclerosis 2 protein.

Within the rheumatoid joint, fibroblast-like synoviocytes (FLSs) are major sources of TNF, IL-1β, IL-6, and granulocyte colony-stimulating factor (G-CSF). IL-6, along with IL-1β and IL-23, promotes the differentiation of pathogenic type 17 helper T (T_H17) cells. Pathogenic T_H17 cells produce the neutrophil growth factor granulocyte-macrophage colony-stimulating factor (GM-CSF). G-CSF and GM-CSF drive neutrophil-derived production of TNF and IL-1β. T_H17 cells are also the major producers of IL-17. TNF, IL-17 and IL-1β induce production of matrix metalloproteinases (MMPs) and a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS), which degrade the cartilage matrix. Similarly, production of the type I cytokine IL-12 by macrophages and dendritic cells (DCs) promotes the differentiation of pathogenic T_H1 cells. T_H1 cells produce IFN-γ, which activates macrophages. IL-20 and other cytokines promote bone resorption by osteoclasts. DCs also produce IL-15, which promotes FLS survival and T_H1 differentiation, and IL-21, which promotes follicular helper T (T_FH)-cell differentiation and antibody production.

The cytoplasmic domain of cytokine receptors associates with various JAKs (JAK1, JAK 2, JAK 3 and non-receptor tyrosine-protein kinase 2 (TYK2)). These kinases act via autophosphorylation as well as STAT phosphorylation. Key host inflammatory responses are mediated through these interactions, including those that lead to autoimmune inflammatory diseases such as rheumatoid arthritis. Shown here are the signalling pathways of a select group of cytokines, as well as cytokine receptor dimerization and their association with JAKs. Of note, the figure depicts important interactions in the host defense against infection including the signalling of both type I interferons and interferon-γ (IFNγ). Type I interferons signal via type II cytokine receptors associated with JAK1 and TYK2, whereas IFNγ signals via type II cytokine receptors associated with JAK1 and JAK2. These signalling pathways are particularly important to host antiviral responses. Other signalling pathways mediated by JAK–STAT are important for cellular homeostasis, including lymphocyte production and erythropoeisis. GM-CSF, granulocyte-macrophage colony-stimulating factor; Jakinib, JAK inhibitor.

The JAK–STAT signaling pathway; after cytokine binds to its receptors the associated Janus kinase (JAK) is induced. This results in the phosphorylation of the receptor’s cytoplasmic domain. STAT is recruited after the phosphorylation of the receptor’s cytoplasmic domain which after phosphorylation dimerizes and migrates into the nucleus. In the nucleus STAT binds to its niche in the DNA and induces gene expression.

Inhibition of JAK/STAT-dependent signaling pathways by tofacitinib and ruxolitinib (Source: Koenders MI, van den Berg WB (2015) Janus kinase inhibitors. Trends in Pharmacological Sciences. 36: 189–195. Elsevier, with permission)

The cytoplasmic domain of cytokine receptors associates with various JAKs (JAK1, JAK 2, JAK 3 and non-receptor tyrosine-protein kinase 2 (TYK2)). These kinases act via autophosphorylation as well as STAT phosphorylation. Key host inflammatory responses are mediated through these interactions, including those that lead to autoimmune inflammatory diseases such as rheumatoid arthritis. Shown here are the signalling pathways of a select group of cytokines, as well as cytokine receptor dimerization and their association with JAKs. Of note, the figure depicts important interactions in the host defense against infection including the signalling of both type I interferons and interferon-γ (IFNγ). Type I interferons signal via type II cytokine receptors associated with JAK1 and TYK2, whereas IFNγ signals via type II cytokine receptors associated with JAK1 and JAK2. These signalling pathways are particularly important to host antiviral responses. Other signalling pathways mediated by JAK–STAT are important for cellular homeostasis, including lymphocyte production and erythropoeisis. GM-CSF, granulocyte-macrophage colony-stimulating factor.