Interactions between Glucocorticoids and Cytokines in the Bone Microenvironment

Abstract

Cytokines belonging to the so-called interleukin-6 (IL-6) or gp130 cytokine family, notably IL-6 and IL-11, are known as pro-resorptive cytokines, in that they promote osteoclastogenesis. Glucocorticoid (GC)-induced osteoporosis is admittedly the most frequent secondary osteoporosis. The pathogenesis still has many unresolved issues. Although the effects of GCs on cytokine production and recognition have been extensively studied, little is known about the effects of cytokines on GC action at the target level. We have focused on the effects of IL-6 and IL-11 on specific binding by type II GC receptors (GRs) in two human osteoblast-like cell lines (Saos-2 and MG-63) that have remarkably different constitutive expression of these cytokines and GRs as well. We have provided evidence that IL-6 upregulates GR binding sites, while IL-11 downregulates these sites, as determined by radioligand binding assay and Scatchard analysis. GR affinity (K(d)) did not change after exposure to both cytokines. A number of experiments were consistent with the view that in human osteoblast-like cells, cytokines of the IL-6 family have autocrine modulatory effects on GRalpha (GRbeta is a variant that does not bind specifically in our method). Complex effects of GCs on the system(s) of proinflammatory/anti-inflammatory cytokines and conversely of these cytokines on GC action could account for the dynamics of bone loss in patients given GCs and conceivably having high concentrations of these cytokines in the bone microenvironment.

Multiple and highly divergent IL-11 genes in teleost fish

“…Similar inhibitory effects of cortisol on fish cytokine expression have been reported for carp IL-1β and TNF-α following costimulation of cortisol with LPS or a fish trypanososme lysate (Engelsma et al 2003;Saeij et al 2003). Furthermore, the inhibitibility of constitutive as well as LPSinduced IL-11 expression by glucocorticoids in carp macrophages is in line with reports on the regulation of mammalian IL-11 gene expression and protein release in vitro (Angeli et al 2002;Elias et al 1995;Kim et al 1999).…”

Illuminating the interrelated immune and endocrine adaptations after multiple exposures to short immobilization stress by in vivo blocking of IL-6

“…On the one hand, IL-6 enhanced glucocorticoid action, e.g., by upregulation of GR in lymphoid and osteoblast-like cell lines (3,13,56) and by increasing release of the acute phase proteins [haptoglobin (31) and ␣ 2 -macroglobulin (26,34)] in hepatoma cells. On the other hand, a series of in vivo (25,64) and in vitro (24,65) studies elucidated an antiglucocorticoid effect of IL-6.…”

Bronchial basal cell and epithelial repair

“…In keeping with this, stimuli such as cyclic adenosine monophosphate, lipopolysaccharide, interleukin (IL)-1b, or IL-6 have been shown to upregulate the expression of GRa in different cell lines. [22][23][24] A number of proinflammatory molecules have been shown to be overexpressed in COP 25 and sarcoidosis. 26 Increased expression of Th1 cytokines (interferon-c, IL-2, IL-12, and IL-18) has been reported in sarcoidosis, whereas overexpression of Th2 cytokines (IL-4, IL-5, and IL-13) has been found in IPF lung tissue.…”