title: Human fetal membranes generate distinct cytokine profiles in response to bacterial Toll-like receptor and nod-like receptor agonists.
abstract: Bacterial infection-associated inflammation is thought to be a major cause of preterm premature rupture of membranes. Proinflammatory cytokines, such as interleukin 1B (IL1B), can weaken fetal membranes (FM) by upregulating matrix metalloproteinases and inducing apoptosis. The mechanism by which infection leads to inflammation at the maternal-fetal interface and subsequent preterm birth is thought to involve innate immune pattern recognition receptors (PRR), such as the Toll-like receptors (TLR) and Nod-like receptors (NLR), which recognize pathogen-associated molecular patterns (PAMPs). The objective of this study was to determine the cytokine profile generated by FMs in response to the bacterial TLR and NLR agonists peptidoglycan (PDG; TLR2), lipopolysaccharide (LPS; TLR4), flagellin (TLR5), CpG ODN (TLR9), iE-DAP (Nod1), and MDP (Nod2). PDG, LPS, flagellin, iE-DAP, and MDP triggered FMs to generate an inflammatory response, but the cytokine profiles were distinct for each TLR and NLR agonist, and only IL1B and RANTES were commonly upregulated in response to all five PAMPs. CpG ODN, in contrast, had a mild stimulatory effect only on MCP-1 and primarily downregulated basal FM cytokine production. IL1B secretion induced by PDG, LPS, flagellin, iE-DAP, and MDP was associated with its processing. Furthermore, FM IL1B secretion in response to TLR2, TLR4, and TLR5 activation was caspase 1-dependent, whereas Nod1 and Nod2 induced IL1B secretion independent of caspase 1. These findings demonstrate that FMs respond to different bacterial TLR and NLR PAMPs by generating distinct inflammatory cytokine profiles through distinct mechanisms that are specific to the innate immune PRR activated.
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, Connecticut.
authors.forename: Mai
authors.initials: M
authors.lastname: Hoang
authors.forename: Julie A
authors.initials: JA
authors.lastname: Potter
authors.forename: Stefan M
authors.initials: SM
authors.lastname: Gysler
authors.forename: Christina S
authors.initials: CS
authors.lastname: Han
authors.forename: Seth
authors.initials: S
authors.lastname: Guller
authors.forename: Errol R
authors.initials: ER
authors.lastname: Norwitz
authors.forename: Vikki M
authors.initials: VM
authors.lastname: Abrahams
mesh_terms: D016207:Cytokines / Q000378:metabolism*; D003960:Diaminopimelic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D005321:Extraembryonic Membranes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism*; D005260:Female; D005408:Flagellin / Q000494:pharmacology*; D006801:Humans; D053583:Interleukin-1beta / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology*; D053472:Nod Signaling Adaptor Proteins / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D053473:Nod2 Signaling Adaptor Protein / Q000494:pharmacology; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious / Q000276:immunology / Q000378:metabolism; D051193:Toll-Like Receptors / Q000819:agonists* / Q000235:genetics / Q000378:metabolism
chemical_list: C408982:CPG-oligonucleotide; D016207:Cytokines; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; C429018:NOD2 protein, human; D053472:Nod Signaling Adaptor Proteins; D053473:Nod2 Signaling Adaptor Protein; D009838:Oligodeoxyribonucleotides; D051193:Toll-Like Receptors; D005408:Flagellin; D003960:Diaminopimelic Acid; C034331:N(2)-(gamma-D-glutamyl)-meso-2,2'-diaminopimelic acid
keywords: Nod-like receptors; Toll-like receptors; caspase 1; cytokines; fetal membrane; interleukin 1beta