| First Author | Ilievski V | Year | 2010 |
| Journal | Biol Reprod | Volume | 83 |
| Issue | 5 | Pages | 767-73 |
| PubMed ID | 20650880 | Mgi Jnum | J:168368 |
| Mgi Id | MGI:4888093 | Doi | 10.1095/biolreprod.110.085464 |
| Citation | Ilievski V, et al. (2010) Synergy between viral and bacterial Toll-like receptors leads to amplification of inflammatory responses and preterm labor in the mouse. Biol Reprod 83(5):767-73 |
| abstractText | 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 mug/ml), polyinosinic:cytidylic acid (poly(I:C); a TLR3 ligand, 10 mug/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. |
