title: Platelet-activating factor: a role in preterm delivery and an essential interaction with Toll-like receptor signaling in mice.
abstract: Platelet-activating factor (PAF), a potent phospholipid activator of inflammation that signals through its cognate receptor (platelet-activating factor receptor, PTAFR), has been shown to induce preterm delivery in mice. Toll-like receptors (TLRs) are transmembrane receptors that mediate innate immunity. We have shown previously that Escherichia coli-induced preterm delivery in mice requires TLR signaling via the adaptor protein myeloid differentiation primary response gene 88 (MyD88), but not an alternative adaptor, Toll/IL-1 receptor domain-containing adapter protein-inducing interferon-beta (TRIF). In the present work, we analyzed the role of endogenously produced PAF in labor using mice lacking (knockout [KO]) PAF acetylhydrolase (PAF-AH; the key degrading enzyme for PAF). PAF-AH KO mice are more susceptible to E. coli-induced preterm delivery and inflammation than controls. In peritoneal macrophages, the PTAFR agonist carbamyl PAF induces production of inflammatory markers previously demonstrated to be upregulated during bacterially induced labor, including: inducible nitric oxide synthase (Nos2), the chemokine Ccl5 (RANTES), tumor necrosis factor (Tnf), and level of their end-products (NO, CCL5, TNF) in a process dependent upon both IkappaB kinase and calcium/calmodulin-dependent protein kinase II. Interestingly, this induced expression was completely eliminated not only in macrophages deficient in PTAFR, but also in those lacking either TLR4, MyD88, or TRIF. The dependence of PAF effects upon TLR pathways appears to be related to production of PTAFR itself: PAF-induced expression of Ptafr mRNA was eliminated completely in TLR4 KO and partially in MyD88 and TRIF KO macrophages. We conclude that PAF signaling plays an important role in bacterially induced preterm delivery. Furthermore, in addition to its cognate receptor, PAF signaling in peritoneal macrophages requires TLR4, MyD88, and TRIF.
authors.affiliation: Department of Obstetrics and Gynecology, NorthShore University HealthSystem, Evanston, Illinois varkhaagrawal@gmail.com.
authors.forename: Varkha
authors.initials: V
authors.lastname: Agrawal
authors.affiliation: Department of Microbiology and Immunology, Rosalind Franklin University of Medicine and Science, North Chicago, Illinois.
authors.forename: Mukesh Kumar
authors.initials: MK
authors.lastname: Jaiswal
authors.affiliation: Department of Obstetrics and Gynecology, NorthShore University HealthSystem, Evanston, Illinois.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Ilievski
authors.affiliation: Department of Microbiology and Immunology, Rosalind Franklin University of Medicine and Science, North Chicago, Illinois.
authors.forename: Kenneth D
authors.initials: KD
authors.lastname: Beaman
authors.affiliation: Department of Pediatrics, Division of Neonatology, University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Tamas
authors.initials: T
authors.lastname: Jilling
authors.affiliation: Department of Obstetrics and Gynecology, NorthShore University HealthSystem, Evanston, Illinois Pritzker School of Medicine, University of Chicago, Chicago, Illinois.
authors.forename: Emmet
authors.initials: E
authors.lastname: Hirsch
mesh_terms: D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase / Q000235:genetics / Q000378:metabolism; D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics; D000818:Animals; D002478:Cells, Cultured; D004843:Epistasis, Genetic; D005260:Female; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics; D010972:Platelet Activating Factor / Q000502:physiology*; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious / Q000235:genetics; D047928:Premature Birth / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D051197:Toll-Like Receptor 4 / Q000235:genetics* / Q000378:metabolism
chemical_list: D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; D033942:Adaptor Proteins, Vesicular Transport; D053594:Myeloid Differentiation Factor 88; D010972:Platelet Activating Factor; D051197:Toll-Like Receptor 4; C507780:Myd88 protein, mouse; C476286:Ticam1 protein, mouse; C493487:Tlr4 protein, mouse
keywords: Escherichia coli; cytokines; inflammation; macrophages