RJ Zitnik, NL Whiting and JA Elias
Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06510-8057.

Interleukin (IL)-6 is a pleiotropic cytokine produced by a wide variety of cells including fibroblasts, macrophages, endothelial cells, and T and B lymphocytes. Regulated IL-6 production is an important part of normal biologic homeostasis, and abnormal IL-6 production has been associated with a large number of diseases including asthma and lung allograft rejection. Glucocorticoids are potent anti-inflammatory agents that are widely used to suppress pulmonary inflammation. To further understand the mechanisms underlying this inhibition, we determined whether glucocorticoid compounds regulate human lung fibroblast IL-6 production and characterized the mechanisms of the effects that were noted. These studies demonstrate that glucocorticoids inhibit IL-1-induced IL-6 production in a dose-dependent fashion. A greater than 95% decrease in IL-6 production was seen with 10(-6) and 10(-7) M dexamethasone, prednisolone, and hydrocortisone, and IC50 values for these agents were approximately 5 x 10(-10), 5 x 10(-9), and 10(-8) M, respectively. mRNA analysis demonstrated that these alterations in protein production were associated with proportionate decreases in IL-6 mRNA accumulation, and that this suppression of IL-6 mRNA could be reversed by the glucocorticoid receptor antagonist RU 486. Nuclear run-on studies demonstrated that glucocorticoids inhibit- IL-1-induced IL-6 gene transcription. However, the magnitude of this effect could not fully account for the potency of the glucocorticoid- induced alterations in IL-6 mRNA accumulation and protein production since 10(-6) M dexamethasone caused only a 50% decrease in IL-1-induced IL-6 gene transcription.(ABSTRACT TRUNCATED AT 250 WORDS)

This article has been cited by other articles:

				M. Ando, I.-S. Park, N. Wada, and Y. Takahashi Steroid Supplementation: A Legitimate Pharmacotherapy After Neonatal Open Heart Surgery Ann. Thorac. Surg., November 1, 2005; 80(5): 1672 - 1678. [Abstract] [Full Text] [PDF]

				M. Roth, P. R.A. Johnson, P. Borger, M. P. Bihl, J. J. Rudiger, G. G. King, Q. Ge, K. Hostettler, J. K. Burgess, J. L. Black, et al. Dysfunctional Interaction of C/EBP{alpha} and the Glucocorticoid Receptor in Asthmatic Bronchial Smooth-Muscle Cells N. Engl. J. Med., August 5, 2004; 351(6): 560 - 574. [Abstract] [Full Text] [PDF]

				M. Miyamoto, M. Tomaki, J. Lotvall, and A. Linden {beta}-Adrenoceptor stimulation and neutrophil accumulation in mouse airways Eur. Respir. J., August 1, 2004; 24(2): 231 - 237. [Abstract] [Full Text] [PDF]

				M. Dunser, W. Hasibeder, M. Rieger, and A. J. Mayr Successful therapy of severe pneumonia-associated ARDS after pneumonectomy with ECMO and steroids Ann. Thorac. Surg., July 1, 2004; 78(1): 335 - 337. [Abstract] [Full Text] [PDF]

				S. McKay, S. J. Hirst, M. B.-d. Haas, J. C. de Jongste, H. C. Hoogsteden, P. R. Saxena, and H. S. Sharma Tumor Necrosis Factor-alpha Enhances mRNA Expression and Secretion of Interleukin-6 in Cultured Human Airway Smooth Muscle Cells Am. J. Respir. Cell Mol. Biol., July 1, 2000; 23(1): 103 - 111. [Abstract] [Full Text]

				L. I. McKay and J. A. Cidlowski Molecular Control of Immune/Inflammatory Responses: Interactions Between Nuclear Factor-{kappa}B and Steroid Receptor-Signaling Pathways Endocr. Rev., August 1, 1999; 20(4): 435 - 459. [Abstract] [Full Text] [PDF]

				J. Wang, Z. Zhu, R. Nolfo, and J. A. Elias Dexamethasone regulation of lung epithelial cell and fibroblast interleukin-11 production Am J Physiol Lung Cell Mol Physiol, January 1, 1999; 276(1): L175 - L185. [Abstract] [Full Text] [PDF]

				K. K. Adkins, T. D. Levan, R. L. Miesfeld, and J. W. Bloom Glucocorticoid regulation of GM-CSF: evidence for transcriptional mechanisms in airway epithelial cells Am J Physiol Lung Cell Mol Physiol, August 1, 1998; 275(2): L372 - L378. [Abstract] [Full Text] [PDF]

				T. M. Reyes and C. L. Coe Resistance of central nervous system interleukin-6 to glucocorticoid inhibition in monkeys Am J Physiol Regulatory Integrative Comp Physiol, August 1, 1998; 275(2): R612 - R618. [Abstract] [Full Text] [PDF]

				S. Wakisaka, N. Suzuki, M. Takeno, Y. Takeba, H. Nagafuchi, N. Saito, H. Hashimoto, T. Tomita, T. Ochi, and T. Sakane Involvement of simultaneous multiple transcription factor expression, including cAMP responsive element binding protein and OCT-1, for synovial cell outgrowth in patients with rheumatoid arthritis Ann Rheum Dis, August 1, 1998; 57(8): 487 - 494. [Abstract] [Full Text]

				D. Y. M. LEUNG, M. de CASTRO, S. J. SZEFLER, and G. P. CHROUSOS Mechanisms of Glucocorticoid-Resistant Asthma Ann. N.Y. Acad. Sci., May 1, 1998; 840(1): 735 - 746. [Abstract] [Full Text] [PDF]

				J. A. D. Cooper Jr., J. M. Fuller, K. M. McMinn, and R. R. Culbreth Modulation of Monocyte Chemotactic Protein-1 Production by Hyperoxia: Importance of RNA Stability in Control of Cytokine Production Am. J. Respir. Cell Mol. Biol., April 1, 1998; 18(4): 521 - 525. [Abstract] [Full Text]

				G. Gurujeyalakshmi, M. A. Hollinger, and S. N. Giri Regulation of Transforming Growth Factor-beta 1 mRNA Expression by Taurine and Niacin in the Bleomycin Hamster Model of Lung Fibrosis Am. J. Respir. Cell Mol. Biol., March 1, 1998; 18(3): 334 - 342. [Abstract] [Full Text]

				L. Pei and L. Pei Identification of a Negative Glucocorticoid Response Element in the Rat Type 1Vasoactive Intestinal Polypeptide Receptor Gene J. Biol. Chem., August 23, 1996; 271(34): 20879 - 20884. [Abstract] [Full Text] [PDF]

				G. P. Chrousos The Hypothalamic-Pituitary-Adrenal Axis and Immune-Mediated Inflammation N. Engl. J. Med., May 18, 1995; 332(20): 1351 - 1363. [Full Text] [PDF]