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      Tumor Necrosis Factor α and Interleukin 1β Enhance the Cortisone/Cortisol Shuttle

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          Abstract

          Endogenously released or exogenously administered glucocorticosteroids are relevant hormones for controlling inflammation. Only 11β-hydroxy glucocorticosteroids, but not 11-keto glucocorticosteroids, activate glucocorticoid receptors. Since we found that glomerular mesangial cells (GMC) express 11β-hydroxysteroid dehydrogenase 1 (11β-OHSD1), which interconverts 11-keto glucocorticosteroids into 11β-hydroxy glucocorticosteroids (cortisone/cortisol shuttle), we explored whether 11β-OHSD1 determines the antiinflammatory effect of glucocorticosteroids. GMC exposed to interleukin (IL)-1β or tumor necrosis factor α (TNF-α) release group II phospholipase A2 (PLA2), a key enzyme producing inflammatory mediators. 11β-hydroxy glucocorticosteroids inhibited cytokine-induced transcription and release of PLA2 through a glucocorticoid receptor–dependent mechanism. This inhibition was enhanced by inhibiting 11β-OHSD1. Interestingly, 11-keto glucocorticosteroids decreased cytokine-induced PLA2 release as well, a finding abrogated by inhibiting 11β-OHSD1. Stimulating GMC with IL-1β or TNF-α increased expression and reductase activity of 11β-OHSD1. Similarly, this IL-1β– and TNF-α–induced formation of active 11β-hydroxy glucocorticosteroids from inert 11-keto glucocorticosteroids by the 11β-OHSD1 was shown in the Kiki cell line that expresses the stably transfected bacterial β-galactosidase gene under the control of a glucocorticosteroids response element. Thus, we conclude that 11β-OHSD1 controls access of 11β-hydroxy glucocorticosteroids and 11-keto glucocorticosteroids to glucocorticoid receptors and thus determines the anti-inflammatory effect of glucocorticosteroids. IL-1β and TNF-α upregulate specifically the reductase activity of 11β-OHSD1 and counterbalance by that mechanism their own proinflammatory effect.

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          Most cited references 54

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          Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction.

          A new method of total RNA isolation by a single extraction with an acid guanidinium thiocyanate-phenol-chloroform mixture is described. The method provides a pure preparation of undegraded RNA in high yield and can be completed within 4 h. It is particularly useful for processing large numbers of samples and for isolation of RNA from minute quantities of cells or tissue samples.
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            The PPARalpha-leukotriene B4 pathway to inflammation control.

            Inflammation is a local immune response to 'foreign' molecules, infection and injury. Leukotriene B4, a potent chemotactic agent that initiates, coordinates, sustains and amplifies the inflammatory response, is shown to be an activating ligand for the transcription factor PPARalpha. Because PPARalpha regulates the oxidative degradation of fatty acids and their derivatives, like this lipid mediator, a feedback mechanism is proposed that controls the duration of an inflammatory response and the clearance of leukotriene B4 in the liver. Thus PPARalpha offers a new route to the development of anti- or pro-inflammatory reagents.
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              Immunoregulatory feedback between interleukin-1 and glucocorticoid hormones.

              The production and action of immunoregulatory cytokines, including interleukin-1 (IL-1), are inhibited by glucocorticoid hormones in vivo and in vitro. Conversely, glucocorticoid blood levels were increased by factors released by human leukocytes exposed to Newcastle disease virus preparations. This activity was neutralized by an antibody to IL-1. Therefore the capacity of IL-1 to stimulate the pituitary-adrenal axis was tested. Administration of subpyrogenic doses of homogeneous human monocyte-derived IL-1 or the pI 7 form of human recombinant IL-1 to mice and rats increased blood levels of adrenocorticotropic hormone (ACTH) and glucocorticoids. Another monokine, tumor necrosis factor, and the lymphokines IL-2 and gamma-interferon had no such effects when administered in doses equivalent to or higher than those of IL-1. The stimulatory effect of IL-1 on the pituitary-adrenal axis seemed not to be mediated by the secondary release of products from mature T lymphocytes since IL-1 was endocrinologically active when injected into athymic nude mice. These results strongly support the existence of an immunoregulatory feedback circuit in which IL-1 acts as an afferent and glucocorticoid as an efferent hormonal signal.
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                Author and article information

                Journal
                J Exp Med
                The Journal of Experimental Medicine
                The Rockefeller University Press
                0022-1007
                1540-9538
                21 July 1997
                : 186
                : 2
                : 189-198
                Affiliations
                From the Division of Nephrology, University Hospital of Berne, 3010 Berne, Switzerland
                Author notes

                Address correspondence to Dr. Felix J. Frey, Division of Nephrology, Inselspital, 3010 Berne, Switzerland. Phone: 41-31-632-96-29; FAX: 41-31-632-94-44.

                Article
                2198986
                9221748
                Categories
                Article

                Medicine

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