The first JAK kinase inhibitor to be developed, tofacitinib, inhibits JAK1 and JAK3. These two JAK kinases are required for the signaling pathways induced by multiple cytokines, including all of the receptors that share the cytokine receptor common gamma chain (gc; includes the receptors for IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21), all of the receptors that share gp130 (includes the receptor for IL-6), the receptors for GM-CSF, IL-12, and IL-23, and both type I and type II (i.e., IFN-g) interferon receptors. Tofacitinib has recently been shown to be effective in the treatment of severe rheumatoid arthritis, an autoimmune disease characterized by inflammation of the joints with prominent inflammatory cell infiltrates, autoantibodies, and eventual cartilage and bone destruction. A likely explanation for the therapeutic benefits of tofacitinib in this disease is: Its ability to inhibit the T cell functions that eventually lead to other disease symptoms Its ability to prevent T cell help for B cells producing autoantibodies Its ability to block migration of inflammatory cells into joints Its ability to block innate as well as adaptive immune responses Its ability to prevent T cell proliferation by blocking IL-2 receptor signaling

The first JAK kinase inhibitor to be developed, tofacitinib, inhibits JAK1 and JAK3. These two JAK kinases are required for the signaling pathways induced by multiple cytokines, including all of the receptors that share the cytokine receptor common gamma chain (gc; includes the receptors for IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21), all of the receptors that share gp130 (includes the receptor for IL-6), the receptors for GM-CSF, IL-12, and IL-23, and both type I and type II (i.e., IFN-g) interferon receptors. Tofacitinib has recently been shown to be effective in the treatment of severe rheumatoid arthritis, an autoimmune disease characterized by inflammation of the joints with prominent inflammatory cell infiltrates, autoantibodies, and eventual cartilage and bone destruction. A likely explanation for the therapeutic benefits of tofacitinib in this disease is:

1. Its ability to inhibit the T cell functions that eventually lead to other disease symptoms
2. Its ability to prevent T cell help for B cells producing autoantibodies
3. Its ability to block migration of inflammatory cells into joints
4. Its ability to block innate as well as adaptive immune responses
5. Its ability to prevent T cell proliferation by blocking IL-2 receptor signaling