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HMGB1 and TLR signalling in pregnant myometrial and amnion cells: friend or FOE?
  1. A J Tyson-Capper,
  2. S C Robson,
  3. E A Shiells,
  4. J A Kirby
  1. Newcastle University, Newcastle upon Tyne, UK

Abstract

Infection and Inflammation have been implicated as predisposing factors for preterm labour and preterm birth.1 This mechanism involves bacterial endotoxin binding to Toll-like receptors (TLRs) present on the surface of host cells triggering activation of a cascade of inflammatory events within the uterus. Critically, in the absence of infection, uterine and fetal inflammation still leads to preterm birth and neonatal injury. Furthermore, endogenous ligands, including high mobility group box 1 protein (HMGB1) also bind to and modulate TLR activity.2 Although originally described as a nuclear DNA-binding protein facilitating transcription, extracellular HMGB1 released passively from damaged cells or actively from immune cells is also associated with modulating inflammatory processes. We hypothesise that HMGB1 may play a part in modulating inflammatory responsiveness and TLR signalling pathways linked with many cases of preterm labour/preterm birth.3We report the variable expression profile and sub-cellular distribution of myometrial HMGB1 in preterm (n=8) and term (not in labour, n=12) tissue samples. Using an in vitro amnion-derived cell culture based assay we show that treatment with recombinant HMGB1 (0.1 g/ml) can affect TLR4 activity as well induce secretion of interleukin-6 (IL-6) and monocyte chemotactic protein-1 (MCP-1). Our findings support the notion that endogenous ligands may do the same as endotoxin in myometrial and amnion cells. Pre-exposure of innate immune cells to HMGB1 can induce an endotoxin-tolerant state by suppressing a subsequent inflammatory response to LPS.4 Whether HMGB1 plays a role in TLR signalling events in the human uterus remains an area for future investigation.

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