title: Inhibitory effect of physiological concentrations of cortisol but not estradiol on interleukin (IL)-6 production by human osteoblast-like cell lines with different constitutive IL-6 expression.
abstract: Estrogen deficiency and glucocorticoid excess are two well-known conditions that account for osteoporosis. Interleukin (IL)-6 plays an important role in bone resorption; both estrogens and glucocorticoids are credited with an inhibitory effect on osteoblast production of IL-6. The aim of the study was to investigate whether endogenous hormones, which lead to opposite changes in bone mass, have a common inhibitory effect upon constitutive and inducible IL-6 production by human osteoblast-like cells. We used two human osteosarcoma cell lines (MG-63 and Saos-2) with a different degree of differentiation and constitutive production of IL-6 [2587+/-536 (mean+/-SE) and 3.65+/-0.06 pg/10(6) cells, respectively]. We examined the effects of physiological and supraphysiological concentrations of 17beta-estradiol (E2) and cortisol on basal and IL-1beta-induced IL-6 release in the medium. In all experimental conditions, cellular estrogen receptors (ERs) and glucocorticoid receptors (GRs) were measured by binding assay. Both MG-63 and Saos-2 cell lines had measurable GRs (106 300+/-24 996 and 18 100+/-3215 binding sites/cell, respectively) and ERs (2197+/-377 and 1261+/-66.5 binding sites/cell, respectively). In MG-63 cells, cortisol treatment for 20 h decreased both basal and IL-1beta-induced IL-6 release in a dose-dependent manner; in Saos-2 cells the same effect was apparent for IL-1beta-induced release. Mifepristone (RU-486) did function as partial agonist and antagonist of cortisol. At variance with cortisol, E2 did not exert any effect on IL-6 secretion. Treatment with 1,25(OH)2D3 increased by 100-200% ER concentrations, but did not change ineffectiveness of E2 in modifying IL-6 production; furthermore, when E2 was combined with cortisol, there was no additive effect on cortisol-induced inhibition. The dissociation between glucocorticoid and estrogen effects observed in these human cell lines is a sufficiently robust phenomenon to raise questions about the pathogenetic role of IL-6 in osteoporosis associated with estrogen deficiency. Conversely inhibition of osteoblast production of IL-6 may offer an explanation why bone resorption is not the dominant factor in the pathogenesis of glucocorticoid-induced osteoporosis.
authors.affiliation: Clinica Medica Generale, Dipartimento di Scienze Cliniche e Biologiche, University of Turin, Orbassano-Turin, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Dovio
authors.forename: M L
authors.initials: ML
authors.lastname: Sartori
authors.forename: R G
authors.initials: RG
authors.lastname: Masera
authors.forename: S
authors.initials: S
authors.lastname: Racca
authors.forename: A
authors.initials: A
authors.lastname: Angeli
mesh_terms: D001665:Binding Sites; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004958:Estradiol / Q000378:metabolism / Q000494:pharmacology*; D006727:Hormone Antagonists / Q000494:pharmacology; D006801:Humans; D006854:Hydrocortisone / Q000819:agonists / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D007375:Interleukin-1 / Q000494:pharmacology; D015850:Interleukin-6 / Q000096:biosynthesis* / Q000378:metabolism; D007700:Kinetics; D015735:Mifepristone / Q000494:pharmacology; D010006:Osteoblasts / Q000378:metabolism*; D011485:Protein Binding; D011869:Radioligand Assay; D011960:Receptors, Estrogen / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D014407:Tumor Cells, Cultured; D000093242:Interleukin-6 Inhibitors
chemical_list: D004958:Estradiol; D006727:Hormone Antagonists; D006854:Hydrocortisone; D007375:Interleukin-1; D015850:Interleukin-6; D015735:Mifepristone; D011960:Receptors, Estrogen; D011965:Receptors, Glucocorticoid; D000093242:Interleukin-6 Inhibitors