Intrauterine infection and preterm labor

Abstract

Preterm labor is defined as labor that begins before 37 completed weeks of pregnancy. More than 12% of infants born in the USA are preterm. At least 40% of preterm births are associated with intrauterine infection. Toll-like receptors (TLRs) are members of a family of cell-surface proteins responsible for recognition of a diverse spectrum of bacterial, viral and fungal pathogens. TLRs initiate the host innate (i.e. non-adaptive) immune response, inducing a proinflammatory cascade involving cytokines, chemokines, prostaglandins, and other effector molecules that result in the characteristic phenomena of labor, such as uterine contractions and rupture of fetal membranes. These cascades may also be activated by mechanisms that are not primarily infectious but are accompanied by inflammatory responses. Now that the molecular mechanisms linking infection and labor have been, to a large extent, elucidated, the challenge is to identify points of overlap with non-infectious causes of labor and to find intervention strategies that can minimize the negative impact of preterm delivery.

Figure 1

Overview of proposed pathways of infectious and non-infectious labor. AP-1, activator protein 1; CCL5, chemokine (C-C motif) ligand 5; dsRNA, double-stranded RNA; IL, interleukin; LMW-HA, low molecular weight hyaluronan; LPS, lipopolysaccharide; LTA, lipoteichoic acid; NFκB, nuclear factor κB; PAF, platelet-activating factor; PGN, peptidoglycan; STAT, signal transducers and activators of transcription; TNF, tumor necrosis factor.

Figure 2

Synergy between toll-like receptor (TLR)-2 and TLR3 activation. (a) In vivo: preterm delivery rates in day-14.5 pregnant CD-1 mice following intrauterine administration of peptidoglycan (PGN) (TLR2 agonist) and/or polyinosinic:cytidylic acid [poly(I:C)] (TLR3 agonist). Preterm delivery was defined as delivery of at least one pup within 48 h (all deliveries occurred in <36 h). P-Values are by Fisher’s exact test. (b) In vitro: RAW 264.7 cells were stimulated with either phosphate-buffered saline, PGN (1 g/mL), poly(I:C) (10 g/mL) or both PGN and poly(I:C) for 5 h. Real-time polymerase chain reaction was performed for interleukin (IL)-1β and normalized to the housekeeping gene glyceraldehyde 3-phosphate dehydrogenase (GAPDH). P-Value was calculated for all four treatments simultaneously by analysis of variance. n = 3 replicates per condition. Depicted is a representative example from among three repeat experiments. Similar results were obtained for tumor necrosis factor-α, nitric oxid synthase 2 and chemokine (C-C motif) ligand 5 (CCL5) (not shown). Modified from Ilievski and Hirsch.