Small molecules to the rescue: Inhibition of cytokine signaling in immune-mediated diseases. (December 2017)

• Record Type: Journal Article
• Authors: Gadina, Massimo; Gazaniga, Nathalia; Vian, Laura; Furumoto, Yasuko
• Is Part Of: Journal of autoimmunity. Volume 85(2018)
• Page Start: 20
• Page End: 31
• Publication Date: 2017-12
• Subjects: Cytokines -- Signal transduction -- Drug development -- Inflammation -- Autoimmunity -- Therapy; JAK Janus Kinase -- STAT Signal transducer and activator of transcription -- NF-kB nuclear factor kappa-light-chain-enhancer of activated B cells -- MAPK Mitogen activated protein kinase -- PI3K Phosphatidylinositol-3′-kinases -- TNF tumor necrosis factor -- IL Interleukin -- CSFs Colony stimulating factors -- IFNs Interferons -- DMARDs disease modifying anti rheumatic drugs -- TFs Transcription factors -- X-SCID X-linked severe combined immunodeficiency -- PV polycythemia vera -- HIES hyper-IgE syndrome -- RA rheumatoid arthritis -- AA alopecia areata -- AU alopecia universalis -- MTX methotrexate -- IBD inflammatory bowel disease -- PsA psoriatic arthritis -- AD atopic dermatitis -- GVHD graft versus host disease -- SLE systemic lupus erythematosus -- CANDLE Chronic Atypical Neutrophilic Dermatosis with Lipodystrophy and Elevated temperature -- STING Stimulator of Interferon Genes -- SAVI STING-associated Vasculopathy with Onset in Infancy -- UC ulcerative colitis -- AS ankylosing spondylitis -- TNFRs TNF receptors -- TRADD TNFR-associated death domain protein -- FADD Fas-associated death domain protein -- X-HIM X-Linked hyper-IgM -- EDA-ID ectodermal dysplasia with immunodeficiency -- TLR Toll-like receptors -- NLRP3 NLR family pyrin domain containing 3 -- NLRC4 NLR family CARD domain-containing protein -- IPAF ICE-protease activating factor -- NAIP NLR family apoptosis inhibitory protein -- AIM2 melanoma 2 -- cIAP cellular inhibitor of apoptosis -- NIK NF-kB-inducing kinase -- IKKγ inhibitor of nuclear factor kappa-B kinase -- GWAS genome-wide association studies -- MS Multiple Sclerosis -- SINE selective inhibitors of nuclear export -- PIP2 phosphatidylinositol-(4, 5)-phosphate -- PIP3 phosphatidylinositol-(3, 4, 5)-phosphate -- PTEN phosphatase and tensin homolog -- mTOR mammalian target of rapamycin -- ROR retinoic-acid-orphan-receptor; Autoimmunity -- Periodicals; Autoimmune diseases -- Periodicals; Autoantibodies -- Periodicals; Autoimmune Diseases -- Periodicals; Auto-immunité -- Périodiques; Maladies auto-immunes -- Périodiques; Electronic journals; 616.978005
• DOI: 10.1016/j.jaut.2017.06.006
• Languages: English
• ISSNs: 0896-8411

Abstract

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-3′-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. Highlights: Cytokines regulates the immune response but are also implicated in the development of several immune mediated diseases. Blocking cytokines or their receptors has been successfully employed to treat patients. Targeting the signal downstream of cytokine receptors has now been employed to generate new and effective drugs.