title: mRNA-binding protein TIA-1 reduces cytokine expression in human endometrial stromal cells and is down-regulated in ectopic endometrium.
abstract: BACKGROUND
  Cytokines and growth factors play important roles in endometrial function and the pathogenesis of endometriosis. mRNAs encoding cytokines and growth factors undergo rapid turnover; primarily mediated by adenosine- and uridine-rich elements (AREs) located in their 3'-untranslated regions. T-cell intracellular antigen (TIA-1), an mRNA-binding protein, binds to AREs in target transcripts, leading to decreased gene expression.
  
  
  OBJECTIVE
  The purpose of this article was to determine whether TIA-1 plays a role in the regulation of endometrial cytokine and growth factor expression during the normal menstrual cycle and whether TIA-1 expression is altered in women with endometriosis.
  
  
  METHODS
  Eutopic endometrial tissue obtained from women without endometriosis (n = 30) and eutopic and ectopic endometrial tissues from women with endometriosis (n = 17) were immunostained for TIA-1. Staining intensities were evaluated by histological scores (HSCOREs). The regulation of endometrial TIA-1 expression by immune factors and steroid hormones was studied by treating primary cultured human endometrial stromal cells (HESCs) with vehicle, lipopolysaccharide, TNF-α, IL-6, estradiol, or progesterone, followed by protein blot analyses. HESCs were engineered to over- or underexpress TIA-1 to test whether TIA-1 regulates IL-6 or TNF-α expression in these cells.
  
  
  RESULTS
  We found that TIA-1 is expressed in endometrial stromal and glandular cells throughout the menstrual cycle and that this expression is significantly higher in the perimenstrual phase. In women with endometriosis, TIA-1 expression in eutopic and ectopic endometrium was reduced compared with TIA-1 expression in eutopic endometrium of unaffected control women. Lipopolysaccharide and TNF-α increased TIA-1 expression in HESCs in vitro, whereas IL-6 or steroid hormones had no effect. In HESCs, down-regulation of TIA-1 resulted in elevated IL-6 and TNF-α expression, whereas TIA-1 overexpression resulted in decreased IL-6 and TNF-α expression.
  
  
  CONCLUSIONS
  Endometrial TIA-1 is regulated throughout the menstrual cycle, TIA-1 modulates the expression of immune factors in endometrial cells, and downregulation of TIA-1 may contribute to the pathogenesis of endometriosis.
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences (H.M.K., E.A., A.T., O.G.-K., M.D.L., H.K., C.M.P.D., G.C., C.F., E.S.) and Department of Pathology (O.S.), Yale School of Medicine, New Haven, Connecticut 06520-8063; and Department of Obstetrics and Gynecology (C.B.K.), Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania 19107.
authors.forename: Hakan Mete
authors.initials: HM
authors.lastname: Karalok
authors.forename: Ebru
authors.initials: E
authors.lastname: Aydin
authors.forename: Ozlen
authors.initials: O
authors.lastname: Saglam
authors.forename: Aysenur
authors.initials: A
authors.lastname: Torun
authors.forename: Ozlem
authors.initials: O
authors.lastname: Guzeloglu-Kayisli
authors.forename: Maria D
authors.initials: MD
authors.lastname: Lalioti
authors.forename: Helena
authors.initials: H
authors.lastname: Kristiansson
authors.forename: Cindy M P
authors.initials: CM
authors.lastname: Duke
authors.forename: Gina
authors.initials: G
authors.lastname: Choe
authors.forename: Clare
authors.initials: C
authors.lastname: Flannery
authors.forename: Caleb B
authors.initials: CB
authors.lastname: Kallen
authors.forename: Emre
authors.initials: E
authors.lastname: Seli
mesh_terms: D000328:Adult; D002469:Cell Separation; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis*; D015536:Down-Regulation; D004715:Endometriosis / Q000378:metabolism; D004717:Endometrium / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D004967:Estrogens / Q000494:pharmacology; D005260:Female; D015870:Gene Expression / Q000187:drug effects / Q000502:physiology; D005822:Genetic Vectors; D006801:Humans; D008597:Menstrual Cycle / Q000378:metabolism; D039102:Poly(A)-Binding Proteins / Q000096:biosynthesis* / Q000494:pharmacology*; D011374:Progesterone / Q000494:pharmacology; D017154:Stromal Cells / Q000187:drug effects / Q000378:metabolism*; D000074019:T-Cell Intracellular Antigen-1
chemical_list: D016207:Cytokines; D004967:Estrogens; D039102:Poly(A)-Binding Proteins; D000074019:T-Cell Intracellular Antigen-1; C071558:TIA1 protein, human; D011374:Progesterone