title: Autocrine up-regulation of glucocorticoid receptors by interleukin-6 in human osteoblast-like cells.
abstract: Interleukin (IL)-6 is a bone-resorbing cytokine that acts primarily on osteoclast progenitors to stimulate both proliferation and differentiation. Glucocorticoids (GC) down-regulate IL-6 synthesis in different cell types, including osteoblasts. Given the fact that bone remodeling is a tightly controlled process, it is reasonable to think of auto-regulatory mechanisms in the bone microenvironment able to prevent excess IL-6 production. We have studied two human osteosarcoma cell lines (Saos-2 and MG-63) with different degrees of differentiation and different constitutive IL-6 production (3.4 +/- 0.2 (mean +/- SE) and 2,898 +/- 401 pg/10(6) cells, respectively). We measured the expression of glucocorticoid receptor (GR) in terms of specific binding sites after exposure of cells to different amounts of IL-6. Incubation for 20 hours with IL-6 at increasing concentrations up to 2,000 pg/ml yielded significant increase of GR binding sites in both cell lines. IL-6 was also able to revert the inhibitory effect of dexamethasone (1 microM) on GR in both cell lines. In MG-63 cells, that express higher concentrations of GR, IL-6 deprivation via a specific anti-IL-6 antibody (100 ng/ml) significantly decreased GR, as it was noticed, although to a lesser degree, using a specific anti-IL-6 receptor antibody. In Saos-2, cells that express lower concentrations of GR, a 40-hour treatment with human IL-1beta (10 ng/ml) significantly increased both IL-6 production and GR. This latter effect was completely abolished by co-treating the cells with the anti-IL-6 antibody. Our data are consistent with an autocrine up-regulation of GR expression by IL-6 in human osteoblast-like cells. This phenomenon, which is also relevant to paracrine cell-to-cell communication, subserves a feedback loop in the bone microenvironment that restrains excess inducible IL-6 production. In patients having high levels of IL-6 and given GCs, it could offer an additional explanation for the biphasic pattern of bone loss in the course of therapy.
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: R G
authors.initials: RG
authors.lastname: Masera
authors.forename: M L
authors.initials: ML
authors.lastname: Sartori
authors.forename: S
authors.initials: S
authors.lastname: Racca
authors.forename: A
authors.initials: A
authors.lastname: Angeli
mesh_terms: D000911:Antibodies, Monoclonal / Q000494:pharmacology; D019898:Autocrine Communication; D002478:Cells, Cultured; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology; D015850:Interleukin-6 / Q000494:pharmacology*; D010006:Osteoblasts / Q000187:drug effects / Q000378:metabolism*; D011965:Receptors, Glucocorticoid / Q000096:biosynthesis*; D019947:Receptors, Interleukin-6 / Q000037:antagonists & inhibitors / Q000276:immunology; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
chemical_list: D000911:Antibodies, Monoclonal; D007375:Interleukin-1; D015850:Interleukin-6; D011965:Receptors, Glucocorticoid; D019947:Receptors, Interleukin-6