title: Modulation of 11beta-hydroxysteroid dehydrogenase isozymes by proinflammatory cytokines in osteoblasts: an autocrine switch from glucocorticoid inactivation to activation.
abstract: Tissue damage by proinflammatory cytokines is attenuated at both systemic and cellular levels by counter anti-inflammatory factors such as corticosteroids. Target cell responses to corticosteroids are dependent on several factors including prereceptor regulation via local steroidogenic enzymes. In particular, two isozymes of 11beta-hydroxysteroid dehydrogenase (11beta-HSD), by interconverting hormonally active cortisol (F) to inactive cortisone (E), regulate the peripheral action of corticosteroids 11beta-HSD1 by converting E to F and 11beta-HSD2 by inactivating F to E. In different in vitro and in vivo systems both 11beta-HSD isozymes have been shown to be expressed in osteoblasts (OBs). Using the MG-63 human osteosarcoma cell-line and primary cultures of human OBs, we have studied the regulation of osteoblastic 11beta-HSD isozyme expression and activity by cytokines and hormones with established roles in bone physiology. In MG-63 cells, interleukin-1beta (IL-1beta) and tumor necrosis factor alpha (TNF-alpha) potently inhibited 11beta-HSD2 activity (cortisol-cortisone conversion) and messenger RNA (mRNA) levels in a dose-dependent manner while stimulating reciprocal expression of 11beta-HSD1 mRNA and activity (cortisone-cortisol conversion). A similar rise in 11beta-HSD1 reductase activity also was observed in primary cultures of OBs treated with 10 ng/ml TNF-alpha. Pretreatment of MG-63 cells with 0.1 ng/ml IL-1beta resulted in increased cellular sensitivity to physiological glucocorticoids as shown by induction of serum and glucocorticoid-inducible kinase (SGK; relative increase with 50 nM F but no IL-1beta pretreatment 1.12 +/- 0.34; with pretreatment 2.63 +/- 0.50; p < 0.01). These results highlight a novel mechanism within bone cells whereby inflammatory cytokines cause an autocrine switch in intracellular corticosteroid metabolism by disabling glucocorticoid inactivation (11beta-HSD2) while inducing glucocorticoid activation (11beta-HSD1). Therefore, it can be postulated that some of the effects of proinflammatory cytokines within bone (e.g., periarticular erosions in inflammatory arthritis) are mediated by this mechanism.
authors.affiliation: Division of Medical Sciences, University of Birmingham, Queen Elizabeth Hospital, Edgbaston, United Kingdom.
authors.forename: M S
authors.initials: MS
authors.lastname: Cooper
authors.forename: I
authors.initials: I
authors.lastname: Bujalska
authors.forename: E
authors.initials: E
authors.lastname: Rabbitt
authors.forename: E A
authors.initials: EA
authors.lastname: Walker
authors.forename: R
authors.initials: R
authors.lastname: Bland
authors.forename: M C
authors.initials: MC
authors.lastname: Sheppard
authors.forename: M
authors.initials: M
authors.lastname: Hewison
authors.forename: P M
authors.initials: PM
authors.lastname: Stewart
mesh_terms: D042842:11-beta-Hydroxysteroid Dehydrogenases; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism* / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D005938:Glucocorticoids / Q000378:metabolism*; D006801:Humans; D006913:Hydroxysteroid Dehydrogenases / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D017874:Immediate-Early Proteins; D007249:Inflammation / Q000378:metabolism; D007375:Interleukin-1 / Q000378:metabolism / Q000494:pharmacology; D007527:Isoenzymes / Q000187:drug effects; D009687:Nuclear Proteins; D010006:Osteoblasts / Q000187:drug effects / Q000378:metabolism*; D012516:Osteosarcoma / Q000201:enzymology; D017346:Protein Serine-Threonine Kinases / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000494:pharmacology; D000099184:Serum-Glucocorticoid Regulated Kinases
chemical_list: D042842:11-beta-Hydroxysteroid Dehydrogenases; D016207:Cytokines; D005938:Glucocorticoids; D006913:Hydroxysteroid Dehydrogenases; D017874:Immediate-Early Proteins; D007375:Interleukin-1; D007527:Isoenzymes; D009687:Nuclear Proteins; D017346:Protein Serine-Threonine Kinases; D014409:Tumor Necrosis Factor-alpha; D000099184:Serum-Glucocorticoid Regulated Kinases