Programming of immune responsiveness by end-organ metabolism of glucocorticoids.

11beta-Hydroxysteroid Dehydrogenase Type 1 (11betaHSD1) catalyzes the conversion of C11-keto-glucocorticoids (GCs) to bioactive C11-hydroxy-GCs, thereby generating activating ligands for the glucocorticoid receptor. We demonstrate that immune cells of both lymphoid (immature thymocytes, CD4+/CD8+ T cells and B220+ B cells) and myeloid (CD11b+ macrophages (M-phi-s). CD11c+ dendrite cells) lineages possess 11betaHSD1 reductase activity. Activation of wild-type, but not 11betaHSD1-/- CD4+ T cells in the presence of C11-keto-GCs attenuates IFN-gamma and IL-2 production. The ability of 11betaHSD1+/+ CD4+ T cells to generate bioactive GCs via intracellular 11betaHSD1 allows a degree of autonomous control over lymphocyte biology and effector functions. Mice deficient in 11betaHSD1 exhibit a proinflammatory phenotype in vivo, as evidenced by the accelerated weight loss and elevated serum TNFalpha, IL-12p40 levels following LPS challenge. 11betaHSD1-/- splenic M-phi-s (splnM-phi-s) and B cells contribute to the inflammatory phenotype since they over express inflammatory cytokines following LPS stimulation. 11betaHSD1+/+ and 11betaHSD1-/- bone marrow derived M-phi-s (BMM-phi-s) acquire and inflammatory phenotype only following conditioning with low levels of GCs, suggesting the hyperresponsiveness of 11betaHSD1-/- splinM-phi-s does not result from intrinsic 11betaHSD1 deficiency. Instead, the proinflammatory phenotype of 11betaHSD1-/- splnM-phi-s results from differential differentiation within the 11betaHSD1-/- host microenvironment, when plasma GC levels are moderately elevated. The overproduction of inflammatory cytokines by GC-conditioned BMM-phi-s and 11betaHSD1-/- splnM-phi-s appears to result from increased activation of the NFkB and MAP kinase signaling cascades, and an attenuation of P13K-dependent Akt activation. Additionally, 11betaHSD1-/- splnM-phi-s and GC conditioned BMM-phi-s express significantly more Src-homology 2 containing 5' phosphatase 1 (SHIP1), which appears to be responsible for the depression in Akt activation. The presence of neutralizing antibodies for TGFbeta abrogates the ability of GCs to enhance SHIP1 expression in BMM-phi-s, suggesting GCs upregulate SHIP1 expression via induction to TGF-beta expression. Consistently, cultures of GC-conditioned BMM-phi-s and CD11b- immune cells obtained from the BM and spleen 11betaHSD1-/- mice express increased levels of bioactive TGFbeta. Our results suggest that modest elevations in micro-environmental GC levels can modify M-phi differentiation and thereby influence subsequent responses to stimulation.