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Macrophages from 11-Hydroxysteroid Dehydrogenase Type 1-Deficient Mice Exhibit an Increased Sensitivity to Lipopolysaccharide Stimulation Due to TGF--Mediated Up-Regulation of SHIP1 Expression

Department of Pathology, School of Medicine, University of Utah, Salt Lake City, UT 84132

11-Hydroxysteroid dehydrogenase type 1 (11HSD1) performs end-organ metabolism of glucocorticoids (GCs) by catalyzing the conversion of C₁₁-keto-GCs to C₁₁-hydroxy-GCs, thereby generating activating ligands for the GC receptor. In this study, we report that 11HSD1^–/– mice are more susceptible to endotoxemia, evidenced by increased weight loss and serum TNF-, IL-6, and IL-12p40 levels following LPS challenge in vivo. Peritoneal and splenic macrophage (splnM) from these genetically altered mice overproduce inflammatory cytokines following LPS stimulation in vitro. Inflammatory cytokine overexpression by 11HSD1^–/– splnM results from an increased activation of NF-B- and MAPK-signaling cascades and an attenuated PI3K-dependent Akt activation. The expression of SHIP1 is augmented in 11HSD1^–/– M and contributes to inflammatory cytokine production because overexpression of SHIP1 in primary bone marrow M (BMM) leads to a similar type of hyperresponsiveness to subsequent LPS stimulation. 11HSD1^+/+ and 11HSD1^–/– BMM responded to LPS similarly. However, 11HSD1^–/– BMM derived in the presence of elevated GC levels up-regulated SHIP1 expression and increased their capacity to produce inflammatory cytokines following their activation with LPS. These observations suggest the hyperresponsiveness of 11HSD1^–/– splnM results from myeloid cell differentiation in the presence of moderately elevated GC levels found within 11HSD1^–/– mice. GC-conditioning of BMM enhanced SHIP1 expression via up-regulation of bioactive TGF-. Consistently, TGF- protein expression was increased in unstimulated CD11b^– cells residing in the BM and spleen of 11HSD1^–/– mice. Our results suggest that modest elevations in plasma GC levels can modify the LPS responsiveness of M by augmenting SHIP1 expression through a TGF--dependent mechanism.

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¹ Address correspondence and reprint requests to Dr. Raymond A. Daynes, Department of Pathology, 5B412 School of Medicine, University of Utah, 30 North 1900 East, Salt Lake City, UT 84132-2501. E-mail address: daynes.office{at}path.utah.edu

² Abbreviations used in this paper: GC, glucocorticoid; GR, GC receptor; GRE, GC response element; 11BHSD1, 11-hydroxysteroid dehydrogenase type 1; M, macrophage; BM, bone marrow; WT, wild type; PEM, peritoneal-elicited M; splnM, splenic M; PIP₃, PI(3,4,5)P₃.