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Rheumatoid arthritis is characterized by the presence of multiple proinflammatory cytokines, which stimulate inflammation. Biological disease-modifying antirheumatic drugs can bind soluble cytokines or soluble receptors in the extracellular space and selectively block a specific cytokine pathway. Since many cytokines are involved in rheumatoid arthritis, researchers have focused on blocking the intracellular portion of the signaling cascade, which may result in broader cytokine inhibition. Many cytokines involved in rheumatoid arthritis rely on intracellular Janus kinases, or JAKs, to propagate their signals. There are 4 types of JAKs. JAKs are implicated in cell growth, survival, development and cell differentiation. JAKs reside on the intracellular portion of the receptor and transmit information from extracellular cytokines to the nucleus. When a cytokine binds to the receptor it activates JAKs resulting in the phosphorylation/activation of STATs. Activated STATs dissociate from the receptor complex and translocate to the nucleus and regulate gene transcription. Different receptors rely on different combinations of JAKs, resulting in different effects. JAK inhibitors vary in terms of their selectivity for different JAKs: some block multiple JAKs, like tofacitinib inhibiting JAK3 and JAK1 (and to a lesser degree JAK2), while others selectively inhibit specific JAKs, like updacitinib selectively inhibiting JAK1. Differences in selectivity influences the types of receptors and affected signaling pathways. Given the range of cytokines that utilize the JAK/STAT pathway for signaling, JAK inhibition has the potential to modulate multiple inflammatory pathways implicated in the pathogenesis of rheumatoid arthritis.
Duration: 02:20
Published: 8/9/2019
Blausen Medical
Scientific and Medical Animations
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