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Toll-like receptor interactions: Tolerance of MyD88-dependent cytokines but enhancement of MyD88-independent interferon-β production

Lookup NU author(s): Dr Anna Broad, Emeritus Professor John Kirby, Professor David Jones


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Toll-like receptors (TLRs) signal through two main pathways: a myeloid differentiation factor (MyD)88-dependent pathway that acts via nuclear factor κB (NF-κB) to induce proinflammatory cytokines such as tumour necrosis factor-α (TNF-α) and a MyD88-independent pathway that acts via type I interferons to increase the expression of interferon-inducible genes. Repeated signalling through TLR4 and a number of other TLRs has been reported to result in a reduction in the subsequent proinflammatory cytokine response, a phenomenon known as TLR tolerance. In this study we have shown that, whilst NF-κB activation and production of TNF-α and interleukin-12 by murine RAW264.7 and J774.2 cells in response to stimulation by TLR4, -5, -7 or -9, was reduced by prior stimulation with TLR4, -5, -7 or -9 ligands, the primary stimulation of TLR3, which does not use the MyD88 pathway, did not reduce the TNF-α or interleukin-12 responses to subsequent TLR stimulation. The response to TLR3 stimulation was not diminished by prior TLR ligand exposure. Furthermore, the production of interferon-β (IFN-β) following stimulation of TLR3 or -4, which is MyD88-independent, was increased by prior activation of TLR4, -5, -7 or -9. In contrast, TLR9 ligand-induced IFN-β production, which is MyD88-dependent, was tolerized by prior TLR stimulation. These results are consistent with differential regulation of MyD88-dependent and MyD88-independent cytokine production following serial activation of TLRs. © 2006 Blackwell Publishing Ltd.

Publication metadata

Author(s): Broad A, Kirby JA, Jones DEJ

Publication type: Article

Publication status: Published

Journal: Immunology

Year: 2006

Volume: 120

Issue: 1

Pages: 103-111

Print publication date: 01/01/2006

ISSN (print): 0019-2805

ISSN (electronic): 1365-2567

Publisher: Wiley-Blackwell Publishing Ltd.


DOI: 10.1111/j.1365-2567.2006.02485.x

PubMed id: 17034424


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