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Beryllium-Induced TNF- Production Is Transcription-Dependent in Chronic Beryllium Disease

Robert H. Hollis Laboratory of Environmental and Occupational Health, Division of Environmental and Occupational Health Sciences, Department of Medicine, Division of Environmental and Occupational Health Sciences, and Integrated Department of Immunology, National Jewish Medical and Research Center; Department of Medicine, Division of Pulmonary Science and Critical Care Medicine, Department of Medicine, Department of Immunology, and Department of Preventive Medicine and Biometrics, University of Colorado Health Sciences Center, Denver, Colorado

Correspondence and requests for reprints should be addressed to Dr. R. T. Sawyer, Division of Allergy, Immunology and Transplantation, NIAID, DHHS, 6610 Rockledge Drive, Room 3103, Bethesda, MD. E-mail: sawyerr{at}niaid.nih.gov

Beryllium (Be)-antigen presentation to Be-specific CD4⁺ T cells from the lungs of patients with chronic beryllium disease (CBD) results in T cell proliferation and TNF- secretion. We tested the hypothesis that Be-induced, CBD bronchoalveolar lavage (BAL) T cell, transcription-dependent, TNF- secretion was accompanied by specific transcription factor upregulation. After 6 h of Be stimulation, CBD BAL cells produced a median of 883 pg/ml TNF- (range, 608–1,275 pg/ml) versus 198 pg/ml (range, 116–245 pg/ml) by unstimulated cells. After 12 h CBD BAL cells produced a median of 2,963 pg/ml (range, 99–9,424 pg/ml) TNF- versus 55 pg/ml (range, 0–454) by unstimulated cells. Using real-time RT-PCR, Be-stimulated TNF- production at 6 h was preceded by a 5-fold increase in TNF- pre-mRNA copy number:-actin copy number (Be median ratio 0.21; unstimulated median ratio 0.04). The median ratio of mature TNF- mRNA:-actin mRNA was upregulated 1.4-fold (Be median ratio 0.17; unstimulated median ratio 0.12). Be exposure in the presence of the transcription inhibitor pentoxifylline (PTX) decreased CBD BAL cell TNF- pre-mRNA levels > 60%, whereas treatment with the mRNA splicing inhibitor 2-aminopurine (2AP) decreased levels 40% relative to Be exposure alone. PTX treatment decreased mature TNF- mRNA levels 50% while 2AP decreased levels > 80%, relative to Be exposure alone. Beryllium exposure specifically upregulated transcription factors AP-1 and NF-B. The data suggest that Be exposure induces transcription-dependent TNF- production, potentially due to upregulation of specific transcription factors.

Key Words: granuloma • T lymphocytes • cytokines • gene regulation • lung

CLINICAL RELEVANCE In chronic beryllium disease, beryllium-antigen–induced TNF- production is transcription-dependent, with up-regulated levels of AP-1 and NF-B. Future strategies aimed at treating this antigen-specific human lung disorder should take this into account.

 

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