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Primer: signal transduction in rheumatic disease—a clinician's guide

Nature Clinical Practice Rheumatology volume 3, pages 651–660 (2007)Cite this article

Abstract

Signaling pathways enable cells to respond and adapt to environmental stimuli. For instance, extracellular ligands, such as proinflammatory cytokines or pathogen components, bind receptors on the surface of cells that trigger downstream signaling cascades driven by enzymes called kinases. Ultimately, kinases activate transcription factors that bind to DNA and alter the expression of target genes, the products of which allow the cell to respond to the initial stimulus. A variety of chronic inflammatory diseases are associated with altered cellular signaling. Some of the signal cascades that are involved in inflammation and autoimmunity include those mediated by mitogen-activated protein kinases, nuclear factor-κB, interferon regulatory factor and Toll-like receptors, NOD-like receptors and the inflammasome, and phosphatidylinositol-3-kinases. Understanding these intracellular pathways might lead to new approaches to the treatment of inflammatory disease, including the use of orally bioavailable small molecules that regulate cytokine function and production.

Key Points

  • Signal transduction is a communication system that provides information to the cell and regulates responses to environmental stress

  • Protein kinases that phosphorylate transcription factors and other molecules have a key role in signal transduction

  • Multiple signaling pathways, including those mediated by mitogen-activated protein kinases, nuclear factor-κB and others, activate immune responses and inflammation by regulating the expression of cytokines and other mediators

  • Signal transduction can potentially be targeted to treat immune-mediated diseases like rheumatoid arthritis and systemic lupus erythematosus

  • Selectivity of signal transduction inhibitors and potential adverse effects related to host defense and homeostasis represent major hurdles to drug development

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Figure 1: Kinase activity and inhibition.
Figure 2: The MAPK signaling cascade.
Figure 3: NF-κB signal transduction.
Figure 4: IRF signaling.

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Authors and Affiliations

  1. SE Sweeney is Assistant Professor of Medicine in the Division of Rheumatology, where GS Firestein is Professor of Medicine and Chief of the Division., Allergy and Immunology at the University of California San Diego, CA, USA,

    Susan E Sweeney & Gary S Firestein

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  1. Susan E Sweeney
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  2. Gary S Firestein
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Corresponding author

Correspondence to Susan E Sweeney.

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The authors declare no competing financial interests.

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Sweeney, S., Firestein, G. Primer: signal transduction in rheumatic disease—a clinician's guide. Nat Rev Rheumatol 3, 651–660 (2007). https://doi.org/10.1038/ncprheum0631

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  • DOI: https://doi.org/10.1038/ncprheum0631

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