Evidence for Activation of Toll-Like Receptor and Receptor for Advanced Glycation End Products in Preterm Birth
Figure 1
The inflammatory biomarkers, alarmins, involved in the development of preterm birth. The most frequently involved pathogens are thought to originate from the genital flora. Although TLR2 and TLR4 bind to components of the gram-positive and -negative bacteria, respectively, they recognize not only infectious agents (exogenous ligands) but also other endogenous ligands. Each TLR family member recognizes a specific pathogen component, upon activation, triggers a signaling cascade leading to pro-inflammatory cytokine production and adaptive immune response. Exogenous ligands for TLRs include bacteria, viruses, fungi, and protozoa as well as their components LPS, HSP and peptidoglycan. The downstream signaling network analysis provides evidence for genes such as NF-kappaB, MAPK, P38MAPK, Akt, and Egr-1. The expression of pro-inflammatory cytokines (notably IL-1beta, IL-6, IL-8, and TNF-alpha) by either the maternal, fetal, or placental tissues has been demonstrated to upregulate the activity of a number of uterine and cervical factors (e.g., prostaglandins and their receptors and several proteases such as matrix metalloproteinases), leading to premature initiation and progression of the parturition process. Activation of the pro-inflammatory and innate immune system via TLRs might be implicated in the pathogenesis of uterine contraction and pPROM in the process of preterm birth. The chronic inflammatory biomarkers, also known as “alarmins”, may be more important for the development of preterm birth. Intracellular “alarmins” are known as DAMPs, which includes HMGB1, HSPs, S100 proteins, and altered matrix proteins. “Alarmins” are secreted from cells upon stimulation, exerting cytokine- and chemokine-like extracellular activities via the RAGE. Increased expression of RAGE has been documented in preterm birth subjects. “Alarmins” might be more important for the development of preterm birth, leading to a chronic and persistent pro-inflammatory state by the activation of TLRs and RAGEs. TLR, Toll-like receptor; LPS, lipopolysaccharide; HSP, heat shock porotein; NF-kappaB, Nuclear Factor-kappaB; MAPK, mitogen-activated protein kinase; Egr-1, Early growth response-1; IL-1beta, interleukin-1beta; TNF-alpha, tumor necrosis factor-alpha; pPROM, preterm premature rupture of membrane; DAMPs, damage-associated molecular patterns; HMGB1, High-mobility group box ; and RAGE, Receptor for advanced glycation end-products.
