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Interleukin-18 Expression in Cystic Fibrosis Lungs*

Edward D. Chan, MD; Hyung-Seok Choi, MD; Carlyne Cool, MD; Frank J. Accurso, MD; Giamila Fantuzzi, PhD
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*From the Divisions of Infectious Diseases (Dr. Fantuzzi) and Pulmonary Sciences and Critical Care Medicine (Dr. Chan), Department of Pathology (Dr. Cool), University of Colorado Health Sciences Center; Cystic Fibrosis Center (Dr. Accurso), Childrens Hospital of Denver; and National Jewish Medical and Research Center (Dr. Choi), Denver, CO.

Correspondence to: Giamila Fantuzzi, PhD, Box B168, Division of Infectious Diseases, Department of Medicine, University of Colorado Health Sciences Center, 4200 East Ninth Ave, Denver, CO 80262; e-mail: giamila.fantuzzi@uchsc.edu



Chest. 2002;121(3_suppl):84S-85S. doi:10.1378/chest.121.3_suppl.84S
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A primary dysregulation of pulmonary inflammation has been proposed as a mechanism leading to airways disease in patients with cystic fibrosis (CF).1 Proinflammatory cytokines, such as tumor necrosis factor-α and interleukin (IL)-8, are elevated in the BAL fluid and sputum of CF patients. Although only a few reports have examined T-helper 1 vs T-helper 2 cytokine expression in CF patients, they suggest a relative defect in T-helper 1 cytokine response. For example, peripheral blood lymphocytes from CF patients produced significantly lower levels of interferon (IFN)-γ compared to lymphocytes from a control group when stimulated in vitro with anti-CD3.2 Furthermore, IFN-γ has been shown to inhibit the production of IL-8 and other proinflammatory cytokines.3 IL-18, a cytokine constitutively produced by macrophages and epithelial cells, induces IFN-γ in T cells. We undertook a study to examine the expression of IL-18 in children with CF. IL-18 levels were measured in the BAL fluid of 17 CF patients (median age, 12 years; age range, 4 months to 25 years) and compared to the levels observed in a control population comprised of 11 subjects with various pathologic conditions. Of the 17 CF subjects, only 3 subjects had detectable IL-18 levels (23 pg/mL, 26 pg/mL, and 37 pg/mL). However, IL-18 was above the detection limit in each subject of the control group (median, 78 pg/mL; mean ± SEM, 261 ± 118 pg/mL) [Fig. 1]. As expected, both IL-8 and IL-1β levels were significantly elevated in the same BAL fluids of CF patients compared to the control group . The IL-1β levels were 124 ± 37 pg/mL in the CF patients and 11 ± 1 pg/mL in the non-CF control subjects (p < 0.001); the IL-8 levels were 645 ± 149 pg/mL in the CF group and 167 ± 101 pg/mL in the non-CF control subjects (p < 0.01). The addition of protease inhibitors to the BAL fluid at the time of collection did not alter IL-18 immunoreactivity, suggesting that neutrophil-derived proteases did not degrade IL-18. In contrast, preliminary results from immunohistochemistry staining of CF lungs for IL-18 revealed abundant expression of IL-18 in the epithelial cells and macrophages compared to lungs from normal control subjects. Ongoing experiments suggest that the BAL of the majority of CF patients contains a factor—not present in the BAL of non-CF patients—that interferes with IL-18 detection. In fact, recovery of exogenous recombinant IL-18 from CF BAL was strongly inhibited compared to non-CF BAL. The presence of this factor would solve the apparent contradiction between reduced levels of IL-18 in the BAL and abundant IL-18 tissue expression in CF patients.

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