Toll-like receptor interactions: tolerance of MyD88-dependent cytokines but enhancement of MyD88-independent interferon-beta production.
Toll-like receptors (TLRs) signal through two main pathways: a myeloid differentiation factor (MyD)88-dependent pathway that acts via nuclear factor kappaB (NF-kappaB) to induce proinflammatory cytokines such as tumour necrosis factor-alpha (TNF-alpha) 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-kappaB activation and production of TNF-alpha 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-alpha 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-beta (IFN-beta) 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-beta 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.
Broad
Andrea
A
The Medical School, University of Newcastle, Newcastle-upon-Tyne, UK.
Kirby
John A
JA
Jones
David E J
DE
D000818:Animals; D015153:Blotting, Western / Q000379:methods; D004731:Endotoxins / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D007108:Immune Tolerance; D016899:Interferon-beta / Q000096:biosynthesis*; D008070:Lipopolysaccharides / Q000276:immunology; D051379:Mice; D053594:Myeloid Differentiation Factor 88 / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology; D051196:Toll-Like Receptor 3 / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000276:immunology; D051193:Toll-Like Receptors / Q000276:immunology*; D051996:Transcription Factor RelA / Q000378:metabolism
D004731:Endotoxins; D008070:Lipopolysaccharides; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; C493487:Tlr4 protein, mouse; D051196:Toll-Like Receptor 3; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D051996:Transcription Factor RelA; D016899:Interferon-beta