Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
8739607 | Journal of Autoimmunity | 2017 | 12 Pages |
Abstract
Cytokines are small, secreted proteins associated with the maintenance of immune homeostasis but also implicated with the pathogenesis of several autoimmune and inflammatory diseases. Biologic agents blocking cytokines or their receptors have revolutionized the treatment of such pathologies. Nonetheless, some patients fail to respond to these drugs or do not achieve complete remission. The signal transduction originating from membrane-bound cytokine receptors is an intricate network of events that lead to gene expression and ultimately regulate cellular functionality. Our understanding of the intracellular actions that molecules such as interleukins, interferons (IFNs) and tumor necrosis factor (TNF) set into motion has greatly increased in the past few years, making it possible to interfere with cytokines' signaling cascades. The Janus kinase (JAK)/signal transducer and activator of transcription (STAT), the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB), the mitogen activated protein kinase (MAPK) and the Phosphatidylinositol-3â²-kinases (PI3K) pathways have all been intensively studied and key steps as well as molecules have been identified. These research efforts have led to the development of a new generation of small molecule inhibitors. Drugs capable of blocking JAK enzymatic activity or interfering with the proteasome-mediated degradation of intermediates in the NF-kB pathway have already entered the clinical arena confirming the validity of this approach. In this review, we have recapitulated the biochemical events downstream of cytokine receptors and discussed some of the drugs which have already been successfully utilized in the clinic. Moreover, we have highlighted some of the new molecules that are currently being developed for the treatment of immune-mediated pathologies and malignancies.
Keywords
PIP3TLRFADDMTXNLRP3Polycythemia veraAIM2TRADDHIESEDA-IDalopecia areataAlopecia universalisNIKDMARDsPIP2NLRC4IKKγSAVIIPAFCSFsGvHDX-SCIDTNFNLR family pyrin domain containing 3TNFRsTFsPI3KIBDRORPSANF-kBmTORJanus kinasecIAPIFNsMAPKpsoriatic arthritisRheumatoid arthritisSTATSINEAnkylosing spondylitisinflammationinterferonsinterleukincellular Inhibitor of ApoptosisInflammatory bowel diseaseDrug developmentautoimmunityAtopic dermatitisTherapyhyper-IgE syndromeCytokinesCANDLETranscription factorstumor necrosis factornuclear factor kappa-light-chain-enhancer of activated B cellsColony Stimulating Factorsphosphatase and tensin homologSystemic lupus erythematosusSLESignal transducer and activator of transcriptionMethotrexatestimulator of interferon genesGenome-wide association studiesGWASinhibitor of nuclear factor kappa-B kinaseMultiple sclerosisNAIPSTINGSignal transductionmammalian target of rapamycinFAS-associated death domain proteinmitogen activated protein kinaseGraft versus host diseaseJAKPtenX-linked severe combined immunodeficiencyUlcerative colitisTNF receptorsToll-like receptors
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Authors
Massimo Gadina, Nathalia Gazaniga, Laura Vian, Yasuko Furumoto,