Modulation of 11β-Hydroxysteroid Dehydrogenase Isozymes by Proinflammatory Cytokines in Osteoblasts: An Autocrine Switch from Glucocorticoid Inactivation to Activation

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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 11β‐hydroxysteroid dehydrogenase (11β‐HSD), by interconverting hormonally active cortisol (F) to inactive cortisone (E), regulate the peripheral action of corticosteroids 11β‐HSD1 by converting E to F and 11β‐HSD2 by inactivating F to E. In different in vitro and in vivo systems both 11β‐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 11β‐HSD isozyme expression and activity by cytokines and hormones with established roles in bone physiology. In MG‐63 cells, interleukin‐1β (IL‐1β) and tumor necrosis factor α (TNF‐α) potently inhibited 11β‐HSD2 activity (cortisol‐cortisone conversion) and messenger RNA (mRNA) levels in a dose‐dependent manner while stimulating reciprocal expression of 11β‐HSD1 mRNA and activity (cortisone‐cortisol conversion). A similar rise in 11β‐HSD1 reductase activity also was observed in primary cultures of OBs treated with 10 ng/ml TNF‐α. Pretreatment of MG‐63 cells with 0.1 ng/ml IL‐1β 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‐1β 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 (11β‐HSD2) while inducing glucocorticoid activation (11β‐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.

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