Decreased interleukin-18 expression in BAL cells and peripheral blood mononuclear cells in adult cystic fibrosis patients

Abstract

Lymphocytes from cystic fibrosis (CF) patients secrete less interferon-gamma (IFN-gamma) upon stimulation compared to controls. Expression of interleukin (IL)-18 as an IFN-gamma inducing factor and of IL-10 as an IL-18 inhibiting factor were determined in bronchoalveolar lavage (BAL) cells from CF patients (n=5) and from normal control subjects (n=9) as well as in peripheral blood mononuclear cells (PBMC) from patients (n=12) and from control subjects (n=9) with RT-PCR. IL-18 and IL-10 serum protein levels were measured using ELISA. BAL cells and PBMC of CF patients expressed significantly less IL-18 compared to controls (p<0.05). There was no significant difference for IL-10 in BAL cells. However, PBMC from patients expressed significantly more IL-10 mRNA (p<0.05). IL-18 serum protein levels were decreased in the patient group, whereas IL-10 serum concentrations were elevated. Stimulation with rhIL-10 reduced IL-18 expression in PBMC from CF patients. Decreased IL-18 expression in CF patients may contribute to decreased IFN-gamma production. IL-10 may contribute to inhibit IL-18 expression in PBMC in CF.

IL-8 Dictates Glycosaminoglycan Binding and Stability of IL-18 in Cystic Fibrosis

“…Of particular interest, we have previously shown that IL-18 plays an important role in the regulation of IL-2 expression by pulmonary CD4 + T lymphocytes in sarcoidosis and that epithelial cell lining fluid concentrations of IL-18 were significantly elevated (15). However, whereas the elastaseantiprotease balance within the sarcoidosis lung is balanced against elastolytic activity (41), supporting the high IL-18 levels within the sarcoidosis lung, within the CF lung, concentrations of NE are extremely high (in the range of 10 26 M) and directly correlate with the low levels of IL-18 recorded in this and in previous studies (5,6). IL-18 is probably best known for its IFN-g-inducing ability and acts in synergy with IL-12 by inducing the production of IFN-g by Th1 cells (42).…”

“…Reduced IL-18 protein levels have been described in CF BALF samples (5,6), and, by way of explanation, inhibition of IL-18 expression by IL-10 was proposed (6). Unexpectedly, however, expression profiles within CF lung epithelial cells and macrophages revealed abundant IL-18 compared with lungs from control subjects (5).…”

“…Dysregulation of cytokine production, with a comparative defect in Th1 immune response, has been identified as a cause of pulmonary inflammation (1,2). In support of this theory, disproportionate concentrations of proinflammatory cytokines have been recorded in CF bronchial samples, including elevated levels of the potent neutrophil chemoattractant IL-8/ CXCL8 (3,4) and, in contrast, dramatically diminished levels of the IFN-g-inducing factor IL-18 (5,6).…”

“…Despite this reasoning, a rationale as to why reduced levels of IL-18 persist in lungs of patients with CF has not been fully elucidated. One investigation has shown that stimulation of CF PBMCs with IL-10 decreased IL-18 expression, thus proposing that IL-10 may inhibit IL-18 in CF mononuclear cells (6). As an alternative explanation it has also been speculated that Pseudomonas aeruginosa-secreted exotoxin A may also decrease IL-18 expression (20).…”

Sputum Biomarkers of Inflammation in Cystic Fibrosis Lung Disease

“…However, a systemic marker may not be sensitive enough to detect a meaningful change in lung disease, given that the inflammatory response to infection in the CF lung is largely confined to the lung. Assessments in blood have included antibodies to Pseudomonas aeruginosa (81)(82)(83) or products of inflammation (84), neutrophil elastase ␣ 1 -antiprotease complexes (63,85), C-reactive protein (CRP) (85,86), and various cytokines from serum or plasma (27,(87)(88)(89)(90)(91)(92)(93)(94)(95)(96)(97), and blood cells themselves (32,33,(98)(99)(100)(101)(102)(103). C-reactive protein is gaining increased recognition as a marker of inflammation for other diseases, but in CF, it is widely variable due to transient increases during pulmonary exacerbations (104,105).…”