title: Gender dimorphism in the gut: mucosal protection by estrogen stimulation of IgA transcytosis.
abstract: BACKGROUND
  Laboratory studies demonstrate gender dimorphism following trauma/hemorrhagic shock (T/HS). These differences have been attributed to estrogen (E2) levels. Maintenance of gut barrier function by E2 following T/HS has been recently described. However, the mechanisms are not clear. The principle humoral defense mechanism of the gut is provided by secretory immunoglobulin IgA. It is transported across intestinal epithelial cells (IEC) by a specific transmembrane protein receptor (polyimmunoglobulin receptor, pIgR). Transport of IgA (transcytosis) may be influenced by a number of factors. We postulated that there may be differences in IgA transcytosis and IEC pIgR expression in response to sex hormones. We studied this in vitro.
  
  
  METHODS
  Confluent HT-29 IEC monolayers were established in a two-chamber cell culture system. E2 or dihydrotestosterone (DHT) was added for 72 hours; then dimeric IgA (dIgA) was added to the basal chamber (4°C, to obtain maximal pIgR binding of dIgA). Apical media were sampled at intervals and recovery of secretory immunoglobulin IgA quantitated by enzyme-linked immunosorbent assay. PIgR expression in HT-29 cells was quantitated as mean fluorescence intensity using flow cytometry. Monolayer integrity was confirmed by serial measurement of transepithelial electrical resistance.
  
  
  RESULTS
  IgA transcytosis increased fourfold in 12-hour versus 3-hour culture periods in the control experiments. A similar finding was noted in the DHT experiments on IgA transcytosis. There were dramatic increases in IgA transcytosis across HT-29 cells exposed to E2.This was apparent at both 3- and 12-hour experimental time points and exhibited a dose-response effect. HT-29 cells cocultured with E2 increased pIgR expression in a time- and dose-dependent fashion. The greatest pIgR expression was noted following coculture of HT-29 cells with E2 for 6 days at the 1.0 μmol/L E2 concentration. The integrity of HT-29 monolayers in both the E2 and DHT treatment groups at T = 0 and 72 hours was assessed and showed no significant differences versus control cells.
  
  
  CONCLUSIONS
  IgA transcytosis was augmented by E2 in a dose-response fashion. This effect was due to augmented intracellular trafficking of IgA and later partly due to increased pIgR expression. The dose-related effects of E2 on IgA transport confirm the findings in animal studies that improved outcomes in females can be related to the estrus cycle.
authors.affiliation: Department of Surgery, Wayne State University, Detroit, Michigan 48201, USA.
authors.forename: Mark E
authors.initials: ME
authors.lastname: Diebel
authors.forename: Lawrence N
authors.initials: LN
authors.lastname: Diebel
authors.forename: David M
authors.initials: DM
authors.lastname: Liberati
mesh_terms: D002478:Cells, Cultured; D004306:Dose-Response Relationship, Immunologic; D004847:Epithelial Cells / Q000502:physiology; D004958:Estradiol / Q000008:administration & dosage / Q000502:physiology*; D005260:Female; D005753:Gastric Mucosa / Q000502:physiology*; D019073:HT29 Cells; D006801:Humans; D056724:Immunity, Humoral / Q000502:physiology; D007070:Immunoglobulin A / Q000502:physiology*; D066298:In Vitro Techniques; D012727:Sex Characteristics; D012771:Shock, Hemorrhagic / Q000503:physiopathology; D057900:Transcytosis / Q000276:immunology / Q000502:physiology*; D014947:Wounds and Injuries / Q000503:physiopathology
chemical_list: D007070:Immunoglobulin A; D004958:Estradiol