Analysis of the transcriptional networks underpinning the activation of murine macrophages by inflammatory mediators.
Macrophages respond to the TLR4 agonist LPS with a sequential transcriptional cascade controlled by a complex regulatory network of signaling pathways and transcription factors. At least two distinct pathways are currently known to be engaged by TLR4 and are distinguished by their dependence on the adaptor molecule MyD88. We have used gene expression microarrays to define the effects of each of three variables--LPS dose, LPS versus IFN-β and -γ, and genetic background--on the transcriptional response of mouse BMDMs. Analysis of correlation networks generated from the data has identified subnetworks or modules within the macrophage transcriptional network that are activated selectively by these variables. We have identified mouse strain-specific signatures, including a module enriched for SLE susceptibility candidates. In the modules of genes unique to different treatments, we found a module of genes induced by type-I IFN but not by LPS treatment, suggesting another layer of complexity in the LPS-TLR4 signaling feedback control. We also observe that the activation of the complement system, in common with the known activation of MHC class 2 genes, is reliant on IFN-γ signaling. Taken together, these data further highlight the exquisite nature of the regulatory systems that control macrophage activation, their likely relevance to disease resistance/susceptibility, and the appropriate response of these cells to proinflammatory stimuli.
The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Scotland, United Kingdom; and.
Sobia
S
Raza
The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Scotland, United Kingdom; and.
Mark W
MW
Barnett
Department of Immunology, Weizmann Institute of Science, Rehovot, Israel.
Zohar
Z
Barnett-Itzhaki
Department of Immunology, Weizmann Institute of Science, Rehovot, Israel.
Ido
I
Amit
The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Scotland, United Kingdom; and.
David A
DA
Hume
The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Scotland, United Kingdom; and tom.freeman@roslin.ed.ac.uk.
Tom C
TC
Freeman
D000818:Animals; D053263:Gene Regulatory Networks / Q000276:immunology*; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D018836:Inflammation Mediators / Q000276:immunology / Q000494:pharmacology*; D016899:Interferon-beta / Q000276:immunology; D007371:Interferon-gamma / Q000276:immunology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008262:Macrophage Activation / Q000187:drug effects* / Q000502:physiology; D008264:Macrophages / Q000166:cytology / Q000276:immunology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D053594:Myeloid Differentiation Factor 88 / Q000276:immunology; D015398:Signal Transduction / Q000187:drug effects* / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000819:agonists / Q000276:immunology; D014158:Transcription, Genetic / Q000187:drug effects* / Q000276:immunology
D000949:Histocompatibility Antigens Class II; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D016899:Interferon-beta; D007371:Interferon-gamma
LPS; gene expression; interferon-β; interferon-γ