(Chest. 2002;121:84S-85S.)
© 2002
American College of Chest Physicians
Interleukin-18 Expression in Cystic Fibrosis Lungs*
Edward D. Chan, MD;
Hyung-Seok Choi, MD;
Carlyne Cool, MD;
Frank J. Accurso, MD and
Giamila Fantuzzi, PhD
*
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{at}uchsc.edu
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-
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)-
compared to
lymphocytes from a control group when stimulated in vitro
with anti-CD3.2
Furthermore, IFN- 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- 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-1ß levels were
significantly elevated in the same BAL fluids of CF patients compared
to the control
group
. The IL-1ß 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.
 |
Footnotes
|
|---|
Abbreviations: CF = cystic fibrosis; IFN = interferon;
IL = interleukin
Dr. Chan is supported by National Institutes of Health grant
1K08HL03625–01, and Dr. Fantuzzi is supported by Cystic Fibrosis
Foundation grant No. FANTUZ0020.
|
References
|
|---|
-
Khan, TZ, Wagener, JS, Bost, T, et al (1995) Early pulmonary inflammation in infants with cystic fibrosis. Am J Respir Crit Care Med 151,1075-1082[Abstract]
-
Moss, RB, Hsu, Y, Olds, L (2000) Cytokine dysregulation in activated cystic fibrosis (CF) peripheral lymphocyte. Clin Exp Immunol 120,518-525[CrossRef][ISI][Medline]
-
Nyhlen, K, Linden, M, Andersson, R, et al (2000) Corticosteroids and interferons inhibit cytokine-induced production of IL-8 by human endothelial cells. Cytokine 12,355-360[CrossRef][ISI][Medline]
TOP
References
