title: Human epididymis protein 4 and secretory leukocyte protease inhibitor in vaginal fluid: relation to vaginal components and bacterial composition.
abstract: Human epididymis protein 4 (HE4) is a protease inhibitor and a recently identified serum biomarker for ovarian cancer. Properties of HE4 in the genital tract of healthy women have not been evaluated. We evaluated associations between HE4 and a second vaginal protease inhibitor, secretory leukocyte protease inhibitor (SLPI), with vaginal concentrations of innate immune mediators or proteases and with the types of vaginal bacterial communities. Vaginal secretions were collected from 18 healthy reproductive age women and assayed by enzyme-linked immunosorbent assay for concentrations of HE4, SLPI, kallikrein 5, cathepsin B, interleukin 1β (IL-1), IL-1 receptor antagonist (IL-1 ra), mannose-binding lectin (MBL), the inducible 70-kDa heat shock protein, and matrix metalloproteinase (MMP)-8. The species composition of vaginal bacterial communities in 16 women was characterized by sequencing amplicons derived from 16S bacterial ribosomal RNA genes. Correlations between any 2 assays were analyzed by the Spearman rank correlation tests. Differences in the concentrations of HE4 and SLPI, and between soluble components and vaginal community types, were analyzed by the Mann-Whitney U tests. Vaginal HE4 concentrations, but not SLPI levels, were positively correlated with levels of IL-1β (P = .0152), IL-1ra (P = .0061), MBL (P = .0100), and MMP-8 (P = .0315). The median vaginal HE4 level, as well as concentrations of MBL, IL-1β, IL-1ra, and MMP-8, was highest when Gardnerella vaginalis dominated a vaginal community. The association between HE4, elevated levels of proteases, immune mediators and high proportions of G vaginalis strongly suggests that HE4 is a component of the proinflammatory immune response in the female genital tract.
authors.affiliation: 1Department of Obstetrics and Gynecology, Division of Immunology and Infectious Diseases, Weill Cornell Medical College, New York, NY, USA.
authors.forename: Theofano
authors.initials: T
authors.lastname: Orfanelli
authors.forename: Aswathi
authors.initials: A
authors.lastname: Jayaram
authors.forename: Georgios
authors.initials: G
authors.lastname: Doulaveris
authors.forename: Larry J
authors.initials: LJ
authors.lastname: Forney
authors.forename: William J
authors.initials: WJ
authors.lastname: Ledger
authors.forename: Steven S
authors.initials: SS
authors.lastname: Witkin
mesh_terms: D001419:Bacteria / Q000145:classification / Q000235:genetics / Q000302:isolation & purification*; D012634:Bodily Secretions / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology*; D004269:DNA, Bacterial / Q000302:isolation & purification; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D007113:Immunity, Innate; D018836:Inflammation Mediators / Q000032:analysis; D064307:Microbiota; D011506:Proteins / Q000378:metabolism*; D012336:RNA, Ribosomal, 16S / Q000302:isolation & purification; D021521:Ribotyping; D053481:Secretory Leukocyte Peptidase Inhibitor / Q000378:metabolism*; D014621:Vagina / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology*; D000081102:WAP Four-Disulfide Core Domain Protein 2
chemical_list: D004269:DNA, Bacterial; D018836:Inflammation Mediators; D011506:Proteins; D012336:RNA, Ribosomal, 16S; C506814:SLPI protein, human; D053481:Secretory Leukocyte Peptidase Inhibitor; D000081102:WAP Four-Disulfide Core Domain Protein 2; C569698:WFDC2 protein, human
keywords: cytokines; human epididymis protein 4; secretory leukocyte protease inhibitor; vagina; vaginal microbiome
references.citation: Sci Transl Med. 2012 May 2;4(132):132ra52
references.pmid: 22553250
references.citation: Cancer Res. 2005 Mar 15;65(6):2162-9
references.pmid: 15781627
references.citation: Tumour Biol. 2013 Feb;34(1):571-6
references.pmid: 23179397
references.citation: PLoS One. 2012;7(11):e47672
references.pmid: 23139753
references.citation: Q J Med. 1993 Sep;86(9):575-82
references.pmid: 8255972
references.citation: Proc Natl Acad Sci U S A. 2011 Mar 15;108 Suppl 1:4680-7
references.pmid: 20534435
references.citation: BMC Microbiol. 2009 Jun 02;9:116
references.pmid: 19490622
references.citation: Infect Immun. 2000 Feb;68(2):688-93
references.pmid: 10639434
references.citation: Genome Res. 2007 Mar;17(3):276-86
references.pmid: 17267810
references.citation: Mod Pathol. 2006 Jun;19(6):847-53
references.pmid: 16607372
references.citation: Int Immunol. 1989;1(2):191-6
references.pmid: 2484883
references.citation: Clin Infect Dis. 2002 Jan 15;34(2):204-9
references.pmid: 11740709
references.citation: Cell. 1997 Feb 7;88(3):417-26
references.pmid: 9039268
references.citation: Infect Immun. 2005 Mar;73(3):1271-4
references.pmid: 15731023
references.citation: Biol Chem. 2008 Jun;389(6):681-8
references.pmid: 18627298
references.citation: Cancer Res. 2003 Jul 1;63(13):3695-700
references.pmid: 12839961
references.citation: Mol Hum Reprod. 2000 Feb;6(2):191-6
references.pmid: 10655462
references.citation: Obstet Gynecol. 2004 Oct;104(4):761-9
references.pmid: 15458899
references.citation: Blood. 1996 Mar 15;87(6):2095-147
references.pmid: 8630372
references.citation: Nat Med. 2013 Jan;19(1):57-64
references.pmid: 23202296
references.citation: Nat Med. 2013 Feb;19(2):227-31
references.pmid: 23353556
references.citation: Proc Natl Acad Sci U S A. 1986 Sep;83(18):6692-6
references.pmid: 3462719
references.citation: Curr Infect Dis Rep. 2013 Apr;15(2):130-5
references.pmid: 23371405
references.citation: J Clin Invest. 2010 Oct;120(10):3421-31
references.pmid: 20921628
references.citation: Biol Reprod. 1991 Aug;45(2):350-7
references.pmid: 1686187
references.citation: Reprod Biol Endocrinol. 2010 Sep 24;8:113
references.pmid: 20868473
references.citation: J Vasc Res. 2013;50(1):52-68
references.pmid: 23172306