title: Inflammatory cytokines differentially up-regulate human endometrial haptoglobin production in women with endometriosis.
abstract: BACKGROUND
  Evidence suggests that eutopic endometrium from women with endometriosis (US-E) has intrinsic functional anomalies compared with women without endometriosis (US-C). We hypothesized that differences in endometrial haptoglobin (eHp) mRNA and protein levels exist between eutopic endometrium from US-E and US-C and that inflammatory mediators may be involved.
  
  
  METHODS
  Endometrial stromal cells and tissue explants from US-E (n = 18) and US-C (n = 18) were cultured (24 h/48 h for cells/explants) with interleukin (IL)-1alpha, -1beta, -6, -8 or tumor necrosis factor-alpha (TNF-alpha) at 0-100 ng/ml. eHp protein in media and mRNA levels were quantified by enzyme-linked immunosorbent assay and quantitative PCR.
  
  
  RESULTS
  In eutopic endometrial stromal cells from US-E, IL-1beta, IL-6 and TNF-alpha (10 ng/ml) increased eHp mRNA levels (P = 0.002, P < 0.001 and P < 0.001, respectively) and eHp protein (P = 0.023, 0.031 and 0.006, respectively) versus control. In endometrial tissues from US-E, IL-1beta, IL-6 and TNF-alpha increased eHp mRNA (P < 0.001, P = 0.017 and P < 0.001, respectively) and eHp protein (P < 0.001, P = 0.007 and 0.039, respectively) versus control. IL-1alpha and IL-8 had small or no effects on isolated endometrial cells or tissues. In US-C, IL-1beta, IL-8 and TNF-alpha each reduced eHp mRNA in endometrial stromal cells (all P < 0.001) versus control; IL-1alpha and IL-6 had no effect. eHp mRNA increased in endometrial tissues from US-C in response to IL-1beta (P = 0.008), IL-6 (P = 0.015) and TNF-alpha (P = 0.031) versus control; IL-1alpha or IL-8 had no effect.
  
  
  CONCLUSIONS
  Endometrium from US-E differentially responds to specific inflammatory cytokines by production of eHp. We propose that up-regulation of endometrial eHp by inflammatory mediators disrupts normal endometrial function and may facilitate the pathogenesis of endometriosis.
authors.affiliation: Department of Obstetrics, Gynecology and Women's Health, The University of Missouri-Columbia, 1 Hospital Drive, N 625 HSC, Columbia, MO 65212, USA. timmsk@health.missouri.edu
authors.forename: K L
authors.initials: KL
authors.lastname: Sharpe-Timms
authors.forename: H
authors.initials: H
authors.lastname: Nabli
authors.forename: R L
authors.initials: RL
authors.lastname: Zimmer
authors.forename: J A
authors.initials: JA
authors.lastname: Birt
authors.forename: J W
authors.initials: JW
authors.lastname: Davis
mesh_terms: D016207:Cytokines / Q000378:metabolism / Q000494:pharmacology*; D004715:Endometriosis / Q000209:etiology / Q000235:genetics* / Q000378:metabolism*; D004717:Endometrium / Q000187:drug effects* / Q000378:metabolism*; D005260:Female; D006242:Haptoglobins / Q000096:biosynthesis* / Q000235:genetics*; D006801:Humans; D066298:In Vitro Techniques; D018836:Inflammation Mediators / Q000378:metabolism / Q000494:pharmacology; D053582:Interleukin-1alpha / Q000494:pharmacology; D053583:Interleukin-1beta / Q000494:pharmacology; D015850:Interleukin-6 / Q000494:pharmacology; D016209:Interleukin-8 / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017154:Stromal Cells / Q000187:drug effects / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects
chemical_list: C508606:CXCL8 protein, human; D016207:Cytokines; C485359:HP protein, human; D006242:Haptoglobins; C508600:IL6 protein, human; D018836:Inflammation Mediators; D053582:Interleukin-1alpha; D053583:Interleukin-1beta; D015850:Interleukin-6; D016209:Interleukin-8; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha