title: Chlamydia trachomatis infection increases fallopian tube PROKR2 via TLR2 and NFκB activation resulting in a microenvironment predisposed to ectopic pregnancy.
abstract: Chlamydia trachomatis and smoking are major risk factors for tubal ectopic pregnancy (EP), but the underlying mechanisms of these associations are not completely understood. Fallopian tube (FT) from women with EP exhibit altered expression of prokineticin receptors 1 and 2 (PROKR1 and PROKR2); smoking increases FT PROKR1, resulting in a microenvironment predisposed to EP. We hypothesize that C. trachomatis also predisposes to EP by altering FT PROKR expression and have investigated this by examining NFκB activation via ligation of the Toll-like receptor (TLR) family of cell-surface pattern recognition receptors. PROKR2 mRNA was higher in FT from women with evidence of past C. trachomatis infection than in those without (P < 0.05), and was also increased in FT explants and in oviductal epithelial cell line OE-E6/E7 infected with C. trachomatis (P < 0.01) or exposed to UV-killed organisms (P < 0.05). The ability of both live and dead organisms to induce this effect suggests ligation of a cell-surface-expressed receptor. FT epithelium and OE-E6/E7 were both found to express TLR2 and TLR4 by immunohistochemistry. Transfection of OE-E6/E7 cells with dominant-negative TLR2 or IκBα abrogated the C. trachomatis-induced PROKR2 expression. We propose that ligation of tubal TLR2 and activation of NFκB by C. trachomatis leads to increased tubal PROKR2, thereby predisposing the tubal microenvironment to ectopic implantation.
authors.affiliation: Centre for Reproductive Biology, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK.
authors.forename: Julie L V
authors.initials: JL
authors.lastname: Shaw
authors.forename: Gillian S
authors.initials: GS
authors.lastname: Wills
authors.forename: Kai-Fai
authors.initials: KF
authors.lastname: Lee
authors.forename: Paddy J
authors.initials: PJ
authors.lastname: Horner
authors.forename: Myra O
authors.initials: MO
authors.lastname: McClure
authors.forename: Vikki M
authors.initials: VM
authors.lastname: Abrahams
authors.forename: Nick
authors.initials: N
authors.lastname: Wheelhouse
authors.forename: Henry N
authors.initials: HN
authors.lastname: Jabbour
authors.forename: Hilary O D
authors.initials: HO
authors.lastname: Critchley
authors.forename: Gary
authors.initials: G
authors.lastname: Entrican
authors.forename: Andrew W
authors.initials: AW
authors.lastname: Horne
mesh_terms: D000328:Adult; D002460:Cell Line; D002690:Chlamydia Infections / Q000150:complications* / Q000473:pathology*; D002692:Chlamydia trachomatis; D005187:Fallopian Tubes / Q000378:metabolism / Q000382:microbiology / Q000473:pathology*; D005260:Female; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D008875:Middle Aged; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D011247:Pregnancy; D011271:Pregnancy, Ectopic / Q000378:metabolism / Q000382:microbiology* / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D018000:Receptors, Peptide / Q000235:genetics / Q000378:metabolism*; D051195:Toll-Like Receptor 2 / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000378:metabolism
chemical_list: D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; C470838:PROKR2 protein, human; D012333:RNA, Messenger; D043562:Receptors, G-Protein-Coupled; D018000:Receptors, Peptide; C495342:TLR2 protein, human; C495345:TLR4 protein, human; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D000072000:NF-KappaB Inhibitor alpha