title: Delineation of the role of Toll-like receptor signaling during peritonitis by a gradually growing pathogenic Escherichia coli.
abstract: In a mouse model of Escherichia coli sepsis characterized by a primary peritoneal infection with 10(4) E. coli and a gradually growing bacterial load, we here show that the early cytokine response and antibacterial defense are dominated by TLR4 via a cooperative action of MyD88 and Trif. Although MyD88(-/-) mice succumbed earlier than WT mice in this E. coli peritonitis model, Trif(-/-) mice displayed a small but significant survival advantage. Despite a large early deficit in antimicrobial defense, TLR4(-/-) mice showed an unaltered survival with normal neutrophil attraction to the peritoneal cavity and normal or even elevated late cytokine release. TLR2 compensated for the lack of TLR4 because TLR2(-/-)/TLR4(-/-) mice did show decreased neutrophil attraction and increased mortality compared with WT mice. Nearly normal early peritoneal TNFα production and lack of early counterregulating systemic levels of the chemoattractant KC were associated with normal peritoneal neutrophil attraction in TLR4(-/-) mice. Late stage increased TNF, IL-1β, IFN-β, and typical IFN-γ production in TLR4(-/-) mice prompted us to evaluate expression of the negative feedback regulator SOCS-1. Lack of early hepatic SOCS-1 expression in TLR4(-/-) mice explained the late innate production of IFN-γ by the liver in TLR4(-/-) mice in this low dose E. coli peritonitis model. In contrast, early TLR4-induced IFN-γ production is described as a hallmark in high dose E. coli peritonitis models. The present study displays how the kinetics of pro- and anti-inflammatory mechanisms are regulated by TLRs during peritonitis by a gradually growing E. coli load and how these kinetics may affect outcome.
authors.affiliation: Center for Infection and Immunity Amsterdam, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands. c.vantveer@amc.uva.nl
authors.forename: Cornelis
authors.initials: C
authors.lastname: van 't Veer
authors.forename: Petra S
authors.initials: PS
authors.lastname: van den Pangaart
authors.forename: Daniëlle
authors.initials: D
authors.lastname: Kruijswijk
authors.forename: Sandrine
authors.initials: S
authors.lastname: Florquin
authors.forename: Alex F
authors.initials: AF
authors.lastname: de Vos
authors.forename: Tom
authors.initials: T
authors.lastname: van der Poll
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D000818:Animals; D016207:Cytokines / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D004926:Escherichia coli; D004927:Escherichia coli Infections / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology; D051379:Mice; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism; D010538:Peritonitis / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D016207:Cytokines; D053594:Myeloid Differentiation Factor 88; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; C507780:Myd88 protein, mouse; C491590:Socs1 protein, mouse; C476286:Ticam1 protein, mouse; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse