title: Macrophages from 11beta-hydroxysteroid dehydrogenase type 1-deficient mice exhibit an increased sensitivity to lipopolysaccharide stimulation due to TGF-beta-mediated up-regulation of SHIP1 expression.
abstract: 11beta-Hydroxysteroid dehydrogenase type 1 (11betaHSD1) performs end-organ metabolism of glucocorticoids (GCs) by catalyzing the conversion of C(11)-keto-GCs to C(11)-hydroxy-GCs, thereby generating activating ligands for the GC receptor. In this study, we report that 11betaHSD1(-/-) mice are more susceptible to endotoxemia, evidenced by increased weight loss and serum TNF-alpha, IL-6, and IL-12p40 levels following LPS challenge in vivo. Peritoneal and splenic macrophage (splnMphi) from these genetically altered mice overproduce inflammatory cytokines following LPS stimulation in vitro. Inflammatory cytokine overexpression by 11betaHSD1(-/-) splnMphi results from an increased activation of NF-kappaB- and MAPK-signaling cascades and an attenuated PI3K-dependent Akt activation. The expression of SHIP1 is augmented in 11betaHSD1(-/-) Mphi and contributes to inflammatory cytokine production because overexpression of SHIP1 in primary bone marrow Mphi (BMMphi) leads to a similar type of hyperresponsiveness to subsequent LPS stimulation. 11betaHSD1(+/+) and 11betaHSD1(-/-) BMMphi responded to LPS similarly. However, 11betaHSD1(-/-) BMMphi 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 11betaHSD1(-/-) splnMphi results from myeloid cell differentiation in the presence of moderately elevated GC levels found within 11betaHSD1(-/-) mice. GC-conditioning of BMMphi enhanced SHIP1 expression via up-regulation of bioactive TGF-beta. Consistently, TGF-beta protein expression was increased in unstimulated CD11b(-) cells residing in the BM and spleen of 11betaHSD1(-/-) mice. Our results suggest that modest elevations in plasma GC levels can modify the LPS responsiveness of Mphi by augmenting SHIP1 expression through a TGF-beta-dependent mechanism.
authors.affiliation: Department of Pathology, School of Medicine, University of Utah, Salt Lake City, UT 84132, USA.
authors.forename: Tian Y
authors.initials: TY
authors.lastname: Zhang
authors.forename: Raymond A
authors.initials: RA
authors.lastname: Daynes
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001402:B-Lymphocytes / Q000187:drug effects / Q000201:enzymology; D001835:Body Weight; D001853:Bone Marrow / Q000378:metabolism; D002478:Cells, Cultured; D004789:Enzyme Activation; D005938:Glucocorticoids / Q000378:metabolism; D000072181:Inositol Polyphosphate 5-Phosphatases; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008907:Mink; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012680:Sensitivity and Specificity; D015398:Signal Transduction; D013154:Spleen / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects*
chemical_list: D005938:Glucocorticoids; D008070:Lipopolysaccharides; D016212:Transforming Growth Factor beta; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D051057:Proto-Oncogene Proteins c-akt; D010744:Phosphoric Monoester Hydrolases; D000072181:Inositol Polyphosphate 5-Phosphatases; C000606433:Inpp5d protein, mouse; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases