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IL-4 fails to regulate in vitro beryllium-induced cytokines in berylliosis

¹ Division of Environmental and Occupational Health Sciences, National Jewish Medical and Research Center, Denver, CO, ² Division of Pulmonary Science and Critical Care Medicine, Dept of Medicine and Dept of Preventive Medicine and Biometrics, University of Colorado Health Sciences Center, Denver, CO, ³ Division of Pulmonary Science and Critical Care Medicine, Dept of Medicine, University of Colorado Health Sciences Center, Denver, CO, and ⁴ National Institute of Occupational Safety and Health, Morgantown, WV, USA

CORRESPONDENCE: L. Maier, National Jewish Medical and Research Center, 1400 Jackson Street, Denver, CO 80206, USA. Fax: 1 3033981452

Keywords: berylliosis, beryllium, cytokines, granuloma, IL-4

Received: February 2, 2000
Accepted September 13, 2000

This work was supported in part by Grant HL0785-23, Grant 5 K08 HL03887, Grant R29 ES-06538, and Grant M01 RR00051 from the National Institutes of Health, U.S. Public Health Service.

Bronchoalveolar lavage (BAL) cells from patients with chronic beryllium disease (CBD) have been used to evaluate the beryllium-specific immune response and potential immunotherapeutics. Beryllium induces interferon- (IFN-), interleukin-2 (IL-2), tumour necrosis factor- (TNF-), interleukin-6 (IL-6) and interleukin-10 (IL-10) from BAL cells. An antibody to IL-2 and recombinant human (rHu) IL-10 is able to partially suppress the beryllium-stimulated immune response. To obtain BAL cells, bronchoscopy is required, providing risk to the patient and a limited number of cells to study the immune response. As a result, the objectives of the study were to determine 1) whether CBD peripheral blood mononuclear cells (PBMNs) stimulated with beryllium would produce a similar cytokine pattern as BAL cells, and 2) whether this response could be modulated by interleukin-4 (IL-4), an immunomodulatory cytokine.

CBD and normal individuals' PBMN and BAL cells were stimulated with and without beryllium sulfate. To modulate this antigen-stimulated response, we added rHu IL-4 to the unstimulated and beryllium-stimulated cells. IFN-, IL-2, TNF-, IL-6 and IL-10 cytokine concentrations were determined from cell supernatants by enzyme-linked immunosorbent assays (ELISA), while IL-4 messenger ribonucleic acid (mRNA) was assessed using polymerase chain reaction (PCR).

Beryllium did not stimulate any of these cytokines from normal PBMNs. Increasing levels of IL-6 and TNF- were produced constituitively by CBD PBMNs over time. Compared to the unstimulated CBD PBMNs, beryllium stimulated significant IFN-, TNF-, IL-2, IL-6 and IL-10 production. This response was similar to that stimulated from CBD BAL cells, although of a much lower magnitude. Low levels of IL-4 mRNA were found in CBD and control PBMNs, which were not increased with beryllium stimulation. The beryllium-stimulated cytokine levels were not decreased by the addition of IL-4. IL-4 was unable to downregulate any of these beryllium-stimulated cytokines from CBD BAL cells or increase IL-4 mRNA from either CBD PBMN or BAL cells, and thus is an unlikely immunomodulatory agent in CBD.

From the data, it was concluded that chronic beryllium disease peripheral blood mononuclear cells provide a model to study the beryllium-stimulated immune response. Interleukin-4's inability to downregulate any of the beryllium-stimulated cytokines makes it an unlikely therapeutic candidate in chronic beryllium disease.

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