Synergy between viral and bacterial toll-like receptors leads to amplification of inflammatory responses and preterm labor in the mouse.
Toll-like receptors (TLRs) recognize molecular constituents of pathogens and activate host innate immune responses. TLR2 responds to Gram-positive organisms and components of their cell walls. TLR3 responds to double-stranded RNA (an intermediate in viral replication). A mouse macrophage cell line (RAW 264.7) and freshly obtained mouse peritoneal macrophages were treated in tissue culture for 5 or 10 h with either peptidoglycan (PGN; a TLR2 ligand, 1 μg/ml), polyinosinic:cytidylic acid (poly(I:C); a TLR3 ligand, 10 μg/ml), both PGN and poly(I:C), or neither. Total RNA was extracted, and RT-PCR was performed. A mouse model of preterm birth induced by intrauterine injection of TLR ligands was used to test in vivo effects. Compared to stimulation with either PGN or poly(I:C) alone, stimulation of macrophages with both ligands (whether simultaneously or sequentially) resulted in synergistic expression of inflammatory mediators, including inducible nitric oxide synthase, interleukin 1 beta, tumor necrosis factor alpha, and the chemokine CCL5 (RANTES). Using peritoneal macrophages obtained from mutant and control mice, this synergy was determined to be dependent upon TLR2 and the TLR-related intracellular adaptor proteins MYD88 and TICAM1 (TRIF). Simultaneous administration of both PGN and poly(I:C) to pregnant mice also produced dramatic synergy in the occurrence of preterm delivery. These results support a possible role for viral infection in preterm labor. Synergy in the mechanisms of parturition suggests the existence of a "two-hit" trigger mechanism that minimizes responses to stimuli of limited biological significance while providing an efficient amplification strategy for rapid activation of labor in response to multiple or more severe insults.
Ilievski
Vladimir
V
Department of Obstetrics and Gynecology, NorthShore University HealthSystem, Evanston, Illinois 60201, USA.
Hirsch
Emmet
E
D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics / Q000502:physiology*; D000818:Animals; D002461:Cell Line, Transformed; D005260:Female; D005786:Gene Expression Regulation; D018836:Inflammation Mediators / Q000378:metabolism; D008024:Ligands; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000502:physiology*; D007752:Obstetric Labor, Premature / Q000235:genetics / Q000276:immunology*; D010457:Peptidoglycan / Q000276:immunology*; D011070:Poly I-C / Q000276:immunology*; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious / Q000235:genetics / Q000276:immunology* / Q000382:microbiology / Q000821:virology; D012333:RNA, Messenger / Q000378:metabolism; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000378:metabolism; D051196:Toll-Like Receptor 3 / Q000235:genetics / Q000378:metabolism; D051193:Toll-Like Receptors / Q000235:genetics / Q000378:metabolism*
D033942:Adaptor Proteins, Vesicular Transport; D018836:Inflammation Mediators; D008024:Ligands; D053594:Myeloid Differentiation Factor 88; D010457:Peptidoglycan; D011070:Poly I-C; D012333:RNA, Messenger; D051195:Toll-Like Receptor 2; D051196:Toll-Like Receptor 3; D051193:Toll-Like Receptors; C507780:Myd88 protein, mouse; C476286:Ticam1 protein, mouse; C519703:TLR3 protein, mouse; C493486:Tlr2 protein, mouse