TW Bost, DW Riches, B Schumacher, PC Carre, TZ Khan, JA Martinez and LS Newman
Department of Medicine, National Jewish Center for Immunology and Respiratory Medicine, Denver, Colorado 80206.

Recent evidence suggests that the alveolar macrophage-derived cytokines tumor necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL-1 beta), and interleukin-6 (IL-6) play important roles in granulomatous diseases. Our objective was to quantify the mRNA for these cytokines in beryllium disease, a human granulomatous disease of known etiology. We hypothesized that alveolar macrophages and bronchoalveolar lavage fluid from patients with beryllium disease and sarcoidosis would express increased levels of mRNA and proteins, respectively, for TNF-alpha, IL- 1 beta, and IL-6 compared with those of normal individuals. We performed bronchoalveolar lavage and used a quantitative polymerase chain reaction to determine alveolar macrophage-derived cytokine gene expression. We determined lavage fluid cytokine levels by enzyme-linked immunosorbent assay. In patients with beryllium disease (n = 23), we observed elevated macrophage mRNA expression for TNF-alpha and IL-6 when compared with that of normal subjects (n = 7). Sarcoidosis patients (n = 6) also had increased expression for TNF-alpha and IL-6 compared with that of normal volunteers. IL-1 beta expression was similar in all three groups. In patients with beryllium disease (n = 39), lavage fluid TNF-alpha concentration was higher than that of 16 normal subjects. Lavage fluid IL-1 beta and IL-6 levels did not differ among the groups. This is the first report of macrophage cytokine expression in beryllium disease. These novel findings suggest that macrophage expression of TNF-alpha and IL-6 may be important in the human granulomatous inflammatory response.

This article has been cited by other articles:

				R. T. Sawyer, A. P. Fontenot, T. A. Barnes, C. E. Parsons, B. C. Tooker, L. A. Maier, M. M. Gillespie, E. B. Gottschall, L. Silveira, J. Hagman, et al. Beryllium-Induced TNF-{alpha} Production Is Transcription-Dependent in Chronic Beryllium Disease Am. J. Respir. Cell Mol. Biol., February 1, 2007; 36(2): 191 - 200. [Abstract] [Full Text] [PDF]

				R. P. Baughman, E. E. Lower, D. A. Bradley, L. A. Raymond, and A. Kaufman Etanercept for Refractory Ocular Sarcoidosis: Results of a Double-Blind Randomized Trial Chest, August 1, 2005; 128(2): 1062 - 1047. [Abstract] [Full Text] [PDF]

				R. T. Sawyer, B. J. Day, V. A. Fadok, M. Chiarappa-Zucca, L. A. Maier, A. P. Fontenot, L. Silveira, and L. S. Newman Beryllium-Ferritin: Lymphocyte Proliferation and Macrophage Apoptosis in Chronic Beryllium Disease Am. J. Respir. Cell Mol. Biol., October 1, 2004; 31(4): 470 - 477. [Abstract] [Full Text] [PDF]

				R. T. Sawyer, C. E. Parsons, A. P. Fontenot, L. A. Maier, M. M. Gillespie, E. B. Gottschall, L. Silveira, and L. S. Newman Beryllium-Induced Tumor Necrosis Factor-{alpha} Production by CD4+ T Cells Is Mediated by HLA-DP Am. J. Respir. Cell Mol. Biol., July 1, 2004; 31(1): 122 - 130. [Abstract] [Full Text] [PDF]

				J. P. Utz, A. H. Limper, S. Kalra, U. Specks, J. P. Scott, Z. Vuk-Pavlovic, and D. R. Schroeder Etanercept for the Treatment of Stage II and III Progressive Pulmonary Sarcoidosis Chest, July 1, 2003; 124(1): 177 - 185. [Abstract] [Full Text] [PDF]

				M. Amicosante, F. Berretta, A. Franchi, P. Rogliani, C. Dotti, M. Losi, R. Dweik, and C. Saltini HLA-DP-unrestricted TNF-{alpha} release in beryllium-stimulated peripheral blood mononuclear cells Eur. Respir. J., November 1, 2002; 20(5): 1174 - 1178. [Abstract] [Full Text] [PDF]

				P. Pantelidis, D.S. McGrath, A.M. Southcott, and R.M. du Bois Single-cell analysis: a novel approach to tumour necrosis factor-{alpha} synthesis and secretion in sarcoidosis Eur. Respir. J., November 1, 2002; 20(5): 1179 - 1184. [Abstract] [Full Text] [PDF]

				K. D. SRIVASTAVA, W. N. ROM, J. JAGIRDAR, T.-A. YIE, T. GORDON, and K.-M. TCHOU-WONG Crucial Role of Interleukin-1beta and Nitric Oxide Synthase in Silica-induced Inflammation and Apoptosis in Mice Am. J. Respir. Crit. Care Med., February 15, 2002; 165(4): 527 - 533. [Abstract] [Full Text] [PDF]

				L. A. MAIER, R. T. SAWYER, R. A. BAUER, L. A. KITTLE, P. LYMPANY, D. MCGRATH, R. DUBOIS, E. DANILOFF, C. S. ROSE, and L. S. NEWMAN High Beryllium-stimulated TNF-alpha Is Associated with the -308 TNF-alpha Promoter Polymorphism and with Clinical Severity in Chronic Beryllium Disease Am. J. Respir. Crit. Care Med., October 1, 2001; 164(7): 1192 - 1199. [Abstract] [Full Text] [PDF]

				L.A. Maier, R.T. Sawyer, S.S. Tinkle, L.A. Kittle, E.A. Barker, R. Balkissoon, C. Rose, and L.S. Newman IL-4 fails to regulate in vitro beryllium-induced cytokines in berylliosis Eur. Respir. J., March 1, 2001; 17(3): 403 - 415. [Abstract] [Full Text] [PDF]

				J. Y. Lee, O. Atochina, B. King, L. Taylor, M. Elloso, P. Scott, and M. D. Rossman Beryllium, an Adjuvant That Promotes Gamma Interferon Production Infect. Immun., July 1, 2000; 68(7): 4032 - 4039. [Abstract] [Full Text] [PDF]

				S. Rosseau, P. Hammerl, U. Maus, H.-D. Walmrath, H. Schutte, F. Grimminger, W. Seeger, and J. Lohmeyer Phenotypic characterization of alveolar monocyte recruitment in acute respiratory distress syndrome Am J Physiol Lung Cell Mol Physiol, July 1, 2000; 279(1): L25 - L35. [Abstract] [Full Text] [PDF]

				B. L. Weller, H. Witschi, and K. E. Pinkerton Quantitation and Localization of Pulmonary Manganese Superoxide Dismutase and Tumor Necrosis Factor {alpha} following Exposure to Ozone and Nitrogen Dioxide Toxicol. Sci., April 1, 2000; 54(2): 452 - 461. [Abstract] [Full Text] [PDF]

				S. S. Tinkle, L. A. Kittle, and L. S. Newman Partial IL-10 Inhibition of the Cell-Mediated Immune Response in Chronic Beryllium Disease J. Immunol., September 1, 1999; 163(5): 2747 - 2753. [Abstract] [Full Text] [PDF]

				M. BALTZAN, S. MEHTA, T. H. KIRKHAM, and M. G. COSIO Randomized Trial of Prolonged Chloroquine Therapy in Advanced Pulmonary Sarcoidosis Am. J. Respir. Crit. Care Med., July 1, 1999; 160(1): 192 - 197. [Abstract] [Full Text]

				S. A. A. COMHAIR, M. J. LEWIS, P. R. BHATHENA, J. P. HAMMEL, and S. C. ERZURUM Increased Glutathione and Glutathione Peroxidase in Lungs of Individuals with Chronic Beryllium Disease Am. J. Respir. Crit. Care Med., June 1, 1999; 159(6): 1824 - 1829. [Abstract] [Full Text]

				A. P. Fontenot, B. L. Kotzin, C. E. Comment, and L. S. Newman Expansions of T-cell Subsets Expressing Particular T-cell Receptor Variable Regions in Chronic Beryllium Disease Am. J. Respir. Cell Mol. Biol., April 1, 1998; 18(4): 581 - 589. [Abstract] [Full Text]

				S. Tinkle and L. Newman Beryllium-stimulated release of tumor necrosis factor-alpha, interleukin-6, and their soluble receptors in chronic beryllium disease Am. J. Respir. Crit. Care Med., December 1, 1997; 156(6): 1884 - 1891. [Abstract] [Full Text]

				D. O'Donnell, J Moynihan, G. Finlay, V. Keatings, C. O'Connor, P McLoughlin, and M. Fitzgerald Exhaled nitric oxide and bronchoalveolar lavage nitrite/nitrate in active pulmonary sarcoidosis Am. J. Respir. Crit. Care Med., December 1, 1997; 156(6): 1892 - 1896. [Abstract] [Full Text]

				L. S. Newman, C. S. Rose, and L. A. Maier Sarcoidosis N. Engl. J. Med., April 24, 1997; 336(17): 1224 - 1234. [Full Text] [PDF]