Modulation of 11 beta-hydroxysteroid dehydrogenase isozymes by proinflammatory cytokines in osteoblasts: An autocrine switch from glucocorticoid inactivation to activation

Tissue damage by proinflammatory cytokines is attenuated at both systemic a nd cellular levels by counter anti-inflammatory factors such as corticoster oids. Target cell responses to corticosteroids are dependent on several fac tors including prereceptor regulation via local steroidogenic enzymes. In p articular, two isozymes of 11 beta -hydroxysteroid dehydrogenase (11 beta - HSD), by interconverting hormonally active cortisol (F) to inactive cortiso ne (E), regulate the peripheral action of corticosteroids 11 beta -HSD1 by converting E to F and 11 beta -HSD2 by inactivating F to E, In different in vitro and in vivo systems both 11 beta -HSD isozymes have been shown to be expressed in osteoblasts (OBs), Using the MG-63 human osteosarcoma cell-li ne and primary cultures of human OBs, we have studied the regulation of ost eoblastic 11 beta -HSD isozyme expression and activity by cytokines and hor mones with established roles in bone physiology, In MG-63 cells, interleuki n-lp (IL-1 beta) and tumor necrosis factor alpha (TNF-alpha) potently inhib ited 11 beta -HSD2 activity (cortisol-cortisone conversion) and messenger R NA (mRNA) levels in a dose-dependent manner while stimulating reciprocal ex pression of 11 beta -HSD1 mRNA and activity (cortisone-cortisol conversion) , A similar rise in 11 beta -HSD1 reductase activity also was observed in p rimary cultures of OBs treated with 10 ng/ml TNF-alpha. Pretreatment of MG- 63 cells with 0.1 ng/ml IL-1 beta resulted in increased cellular sensitivit y to physiological glucocorticoids as shown by induction of serum and gluco corticoid-inducible kinase (SGK; relative increase with 50 nM F but no IL-1 beta pretreatment 1.12 +/- 0.34; with pretreatment 2.63 +/- 0.50; p < 0.01 ). These results highlight a novel mechanism within bone cells whereby infl ammatory cytokines cause an autocrine switch in intracellular corticosteroi d metabolism by disabling glucocorticoid inactivation (11 beta -HSD2) while inducing glucocorticoid activation (11 beta -HSD1), Therefore, it can be p ostulated that some of the effects of proinflammatory cytokines within bone (e,g,, periarticular erosions in inflammatory arthritis) are mediated by t his mechanism.