{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T14:07:17Z","timestamp":1787062037153,"version":"build-2736575974"},"reference-count":35,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2012,6,26]],"date-time":"2012-06-26T00:00:00Z","timestamp":1340668800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Arthritis &amp; Rheumatism"],"published-print":{"date-parts":[[2012,7]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>Tissue glucocorticoid (GC) levels are regulated by the GC\u2010activating enzyme 11\u03b2\u2010hydroxysteroid dehydrogenase type 1 (11\u03b2\u2010HSD1). This enzyme is expressed in cells and tissues arising from mesenchymal stromal cells. Proinflammatory cytokines dramatically increase expression of 11\u03b2\u2010HSD1 in stromal cells, an effect that has been implicated in inflammatory arthritis, osteoporosis, obesity, and myopathy. Additionally, GCs act synergistically with proinflammatory cytokines to further increase enzyme expression. The present study was undertaken to investigate the mechanisms underlying this regulation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Gene reporter analysis, rapid amplification of complementary DNA ends (RACE), chemical inhibition experiments, and genetic disruption of intracellular signaling pathways in mouse embryonic fibroblasts (MEFs) were used to define the molecular mechanisms underlying the regulation of 11\u03b2\u2010HSD1 expression.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Gene reporter, RACE, and chemical inhibitor studies demonstrated that the increase in 11\u03b2\u2010HSD1 expression with tumor necrosis factor \u03b1 (TNF\u03b1)\/interleukin\u20101\u03b2 (IL\u20101\u03b2) occurred via the proximal HSD11B1 gene promoter and depended on NF\u2010\u03baB signaling. These findings were confirmed using MEFs with targeted disruption of NF\u2010\u03baB signaling, in which RelA (p65) deletion prevented TNF\u03b1\/IL\u20101\u03b2 induction of 11\u03b2\u2010HSD1. GC treatment did not prevent TNF\u03b1\u2010induced NF\u2010\u03baB nuclear translocation. The synergistic enhancement of TNF\u03b1\u2010induced 11\u03b2\u2010HSD1 expression with GCs was reproduced by specific inhibitors of p38 MAPK. Inhibitor and gene deletion studies indicated that the effects of GCs on p38 MAPK activity occurred primarily through induction of dual\u2010specificity phosphatase 1 expression.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>The mechanism by which stromal cell expression of 11\u03b2\u2010HSD1 is regulated is novel and distinct from that in other tissues. These findings open new opportunities for development of therapeutic interventions aimed at inhibiting or stimulating local GC levels in cells of mesenchymal stromal lineage during inflammation.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/art.34414","type":"journal-article","created":{"date-parts":[[2012,1,31]],"date-time":"2012-01-31T10:29:24Z","timestamp":1328005764000},"page":"2404-2413","source":"Crossref","is-referenced-by-count":40,"title":["Inflammatory regulation of glucocorticoid metabolism in mesenchymal stromal cells"],"prefix":"10.1002","volume":"64","author":[{"given":"Mohammad 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