Abstract
Toll like receptors (TLRs) are pattern-recognition molecules that initiate the innate immune response to pathogens. Pulmonary surfactant protein (SP)-A is an endogenously produced ligand for TLR2 and TLR4. SP-A has been proposed as a fetally produced signal for the onset of parturition in the mouse. We examined the effect of interactions between SP-A and the pathogenic TLR agonists lipopolysaccharide (LPS), peptidoglycan (PGN) and polyinosinic:cytidylic acid (poly(I:C)) (ligands for TLR4, TLR2 and TLR3, respectively) on the expression of inflammatory mediators and preterm delivery. Three types of mouse macrophages (the cell line RAW 264.7, and fresh amniotic fluid and peritoneal macrophages, including macrophages from TLR4 and TLR2 knockout mice) were treated for up to 7 hours with pathogenic TLR agonists with or without SP-A. SP-A alone had no effect upon inflammatory mediators in mouse macrophages and did not independently induce preterm labor. SP-A significantly suppressed TLR ligand-induced expression of inflammatory mediators (interleukin (IL)-1β, tumor necrosis factor (TNF)-α and the chemokine CCL5) via a TLR2 dependent mechanism. In a mouse inflammation-induced preterm delivery model, intrauterine administration of SP-A significantly inhibited preterm delivery, suppressed the expression of proinflammatory mediators and enhanced the expression of the CXCL1 and anti-inflammatory mediator IL-10. We conclude that SP-A acts via TLR2 to suppress TLR ligand-induced preterm delivery and inflammatory responses.
Highlights
Preterm birth is the most important cause of neonatal morbidity and mortality not due to congenital anomalies in the developed world [1]
Binding of Toll like receptors (TLRs) is the initial event in activation of the innate immune system which leads, among other events, to the nuclear translocation of the transcription factor nuclear factor (NF)-kB and the elaboration of a network of inflammatory mediators
surfactant protein (SP)-A alone had no effect upon inflammatory mediators
Summary
Preterm birth is the most important cause of neonatal morbidity and mortality not due to congenital anomalies in the developed world [1]. Up to 40% of cases of preterm labor are associated with infection in the gestational compartment [2]. In individual cases it may be difficult to determine whether infection is a cause or a consequence of labor, it has become clear that infection and inflammation represent important and frequent mechanisms of disease. Toll like receptors (TLRs) are a family of membrane bound proteins that recognize pathogen-associated molecular patterns and mediate innate immune responses [3,4,5,6]. Binding of TLRs is the initial event in activation of the innate immune system which leads, among other events, to the nuclear translocation of the transcription factor nuclear factor (NF)-kB and the elaboration of a network of inflammatory mediators. Our lab and others have shown that preterm labor can be induced in mice by pathogens or pathogen-derived TLR ligands for TLR4 (which recognizes Gram negative bacteria) [7,8,9], TLR2 (which recognizes Gram positive bacteria) [10], TLR3 (which recognizes viral intermediates) [11], and in a synergistic fashion, TLR2 plus TLR3 [12]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
