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Glucocorticoid Conditioning of Myeloid Progenitors Enhances TLR4 Signaling via Negative Regulation of the Phosphatidylinositol 3-Kinase-Akt Pathway¹

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

The immunomodulatory effects of glucocorticoids (GCs) have been described as bimodal, with high levels of GCs exerting immunosuppressive effects and low doses of GCs being immunopermissive. While the mechanisms used by GCs to achieve immunosuppression have been investigated intensely, the molecular mechanisms underlying the permissive effects of GCs remain uncharacterized. Herein, we demonstrate that GC conditioning during the differentiation of myeloid progenitors into macrophages (Ms) results in their enhanced LPS responsiveness, demonstrated by an overexpression of the inflammatory cytokines TNF-, IL-6, and IL-12. Inflammatory cytokine overexpression resulted from an increased activation of NF-B and the MAPK signaling cascade and a reduced activation of the PI3K-Akt pathway following LPS stimulation. GC conditioning during M differentiation induced an increase in the expression of SHIP1, a phosphatase that negatively regulates the PI3K signaling pathway. Small interfering RNA-mediated knockdown of SHIP1 expression increased PI3K-dependent Akt activation and subsequently decreased inflammatory cytokine expression, suggesting GC-mediated up-regulation of SHIP1 expression is responsible for the augmentation in inflammatory cytokine production following LPS stimulation. We also show that splenic Ms purified from normal mice that were implanted with timed-release GC pellets exhibited an enhanced LPS responsiveness and increased SHIP1 expression, indicating that GCs can regulate SHIP1 expression in vivo. Our results suggest that minor fluctuations in physiological levels of endogenous GCs can program endotoxin-responsive hemopoietic cells during their differentiation by regulating their sensitivity to stimulation.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grant AI059242 and Browning Foundation Grant DK55491. T.Y.Z. is supported by National Institutes of Health Department of Health and Human Services National Institute of Diabetes and Digestive and Kidney Diseases Hematology Research Training Grant T32 DK07115.

² Address correspondence and reprint requests to Dr. Raymond A. Daynes, Department of Pathology, University of Utah School of Medicine, 30 North 1900 East, Salt Lake City, UT 84132-2501. E-mail address: daynes.office{at}path.utah.edu

³ Abbreviations used in this paper: GC, glucocorticoid; BMM, bone marrow-derived macrophage; DN, kinase dead; M, macrophage; HPA axis, hypothalamic pituitary adrenal axis; GRE, GC response element; HA, hemagglutinin; p, phosphorylated; PDK, phosphatidylinositol-dependent kinase; ND, normally derived; Akt/PKB, phosphatidylinositol-dependent kinase B; PIP₃, phosphatidylinositol 3,4,5-trisphosphate; IRAK-M, IL-1R-associated kinase myeloid specific; siRNA, small interfering RNA; SOCS-1, suppressor of cytokine signaling-1; WT, wild type.

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