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Toll-like receptor–mediated cytokine production is differentially regulated by glycogen synthase kinase 3

Nature Immunology volume 6, pages 777–784 (2005)Cite this article

Abstract

The cellular mechanisms that directly regulate the inflammatory response after Toll-like receptor (TLR) stimulation are unresolved at present. Here we report that glycogen synthase kinase 3 (GSK3) differentially regulates TLR-mediated production of pro- and anti-inflammatory cytokines. Stimulation of monocytes or peripheral blood mononuclear cells with TLR2, TLR4, TLR5 or TLR9 agonists induced substantial increases in interleukin 10 production while suppressing the release of proinflammatory cytokines after GSK3 inhibition. GSK3 regulated the inflammatory response by differentially affecting the nuclear amounts of transcription factors NF-κB subunit p65 and CREB interacting with the coactivator CBP. Administration of a GSK3 inhibitor potently suppressed the proinflammatory response in mice receiving lipopolysaccharide and mediated protection from endotoxin shock. These findings demonstrate a regulatory function for GSK3 in modulating the inflammatory response.

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Figure 1: E. coli LPS induces the phosphorylation of Akt (Ser473) and GSK3-β (Ser9) through the PI(3)K-Akt pathway in human peripheral blood monocytes.
Figure 2: The PI(3)K pathway differentially modulates pro- and anti-inflammatory cytokine production by inhibition of GSK3.
Figure 3: The siRNA targeting GSK3-β enhances IL-10 and suppresses IL-12p40 by LPS-stimulated monocytes.
Figure 4: Inhibition of GSK3 differentially regulates pro- and anti-inflammatory cytokine production after TLR2, TLR4, TLR5 and TLR9 stimulation.
Figure 5: GSK3 inhibition affects the association of NF-κB p65 and CREB with CBP that regulates the production of IL-10 and IL-12.
Figure 6: The GSK3 inhibitor SB216763 protects mice from endotoxin shock.

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Acknowledgements

Supported in part by the US Public Health Service (DE 08182, DE 14215, DE 09081 and AI 056460).

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Authors and Affiliations

  1. Department of Oral Biology, University of Alabama at Birmingham, Birmingham, 35294-2170, Alabama, USA

    Michael Martin

  2. Department of Microbiology, University of Alabama at Birmingham, Birmingham, 35294-2170, Alabama, USA

    Kunal Rehani & Suzanne M Michalek

  3. Department of Psychiatry, University of Alabama at Birmingham, Birmingham, 35294-2170, Alabama, USA

    Richard S Jope

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Correspondence to Michael Martin.

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Martin, M., Rehani, K., Jope, R. et al. Toll-like receptor–mediated cytokine production is differentially regulated by glycogen synthase kinase 3. Nat Immunol 6, 777–784 (2005). https://doi.org/10.1038/ni1221

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