title: Oestrogens prevent the increase of human serum soluble interleukin-6 receptor induced by ovariectomy in vivo and decrease its release in human osteoblastic cells in vitro.
abstract: OBJECTIVE
  Interleukin-6 (IL-6) seems to be a key mediator of the increased bone loss that follows loss of ovarian function. Based on this and on evidence that oestrogen deficiency may also increase cell sensitivity to IL-6, we studied the effects of ovariectomy and of oestrogen replacement therapy on the serum levels of IL-6 and of soluble IL-6 receptor (sIL-6R) in vivo.
  
  
  METHODS
  Thirty-seven fertile women undergoing surgery for benign uterine diseases were divided into 3 groups and monitored for 12 months: hysterectomized women (n = 9), ovariectomized untreated women (n = 12) and ovariectomized women starting treatment with transdermal estradiol (E2, 50 microg/d) 1 month after surgery (n = 16).
  
  
  RESULTS
  Hysterectomy alone caused no significant changes of sIL6R whereas serum levels of sIL-6R rose progressively after ovariectomy (mean +/- SEM: 31 +/- 9% and 38 +/- 7% over baseline, at 6 and 12 months, respectively; P < 0.01). Oestrogen replacement therapy prevented the increase of sIL6R over a 1-year period. A similar pattern was also found for serum IL-6 but the changes did not reach statistical significance. In ovariectomized (OVX) women there were significant correlations between serum sIL-6R levels and FSH (r = 0.59; P < 0. 01), oestradiol (r = - 0.43; P < 0.01), testosterone (r = - 0.41; P < 0.05), osteocalcin (r = 0.42; P < 0.05) and bone alkaline phosphatase (r = 0.44; P < 0.05). To examine whether oestrogen directly regulates sIL-6R secretion by bone cells, we studied in vitro the basal and phorbol ester (PMA) stimulated release of sIL-6R in a human osteoblastic cell-line (MG-63) and in a tumour-derived osteoclastic cell line (GCT-51). Osteoblastic (but not osteoclastic) cells spontaneously produced considerable amounts of sIL-6R and the protein kinase-C activator PMA (10-8 M) increased the release of sIL-6R by osteoblasts more than 3-fold. More strikingly, 17beta E2 (but not 17alpha) significantly inhibited both the spontaneous- and PMA-induced release of sIL-6R by osteoblastic cells (P < 0.05).
  
  
  CONCLUSIONS
  These results indicate that oestrogen loss causes alterations of the IL-6 system, and that sIL-6R is under the direct inhibitory control of oestrogens both in vivo and in vitro.
authors.affiliation: Cattedra di Medicina Interna, Dipartimento di Medicina Interna e Scienze Biomediche, University of Parma, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Girasole
authors.forename: N
authors.initials: N
authors.lastname: Giuliani
authors.forename: A B
authors.initials: AB
authors.lastname: Modena
authors.forename: G
authors.initials: G
authors.lastname: Passeri
authors.forename: M
authors.initials: M
authors.lastname: Pedrazzoni
mesh_terms: D000469:Alkaline Phosphatase / Q000097:blood; D000704:Analysis of Variance; D015415:Biomarkers / Q000097:blood; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004958:Estradiol / Q000097:blood / Q000494:pharmacology*; D015914:Estrogen Replacement Therapy; D005260:Female; D005640:Follicle Stimulating Hormone / Q000097:blood; D006801:Humans; D007044:Hysterectomy; D010006:Osteoblasts / Q000187:drug effects / Q000378:metabolism; D015675:Osteocalcin / Q000097:blood; D010052:Ovariectomy; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D019947:Receptors, Interleukin-6 / Q000097:blood*; D013739:Testosterone / Q000097:blood; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
chemical_list: D015415:Biomarkers; D004791:Enzyme Inhibitors; D019947:Receptors, Interleukin-6; D015675:Osteocalcin; D013739:Testosterone; D004958:Estradiol; D005640:Follicle Stimulating Hormone; D011493:Protein Kinase C; D000469:Alkaline Phosphatase; D013755:Tetradecanoylphorbol Acetate