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Regulation of interleukin-1ß and interleukin-1ß inhibitor release by human airway epithelial cells

Division of Pulmonary, Allergy and Critical Care Medicine, Dept of Medicine, Temple University School of Medicine, Philadelphia, PA, USA

CORRESPONDENCE: S.G. Kelsen, 761 Parkinson Pavilion, Temple University Hospital, 3401 N. Broad St., Philadelphia, PA, 19140, USA. Fax: 1 2157071481. E-mail: kelsen@temple.edu

Keywords: Airway inflammation, asthma, cytokines

Received: August 4, 2003
Accepted March 29, 2004

This study was supported, in part, by National Institutes of Health (Bethesda, MD, USA) grant number R01 HL52700-04.

In asthma, human airway epithelial cells (HAECs) regulate the intensity of mucosal inflammation, in part, by releasing the pro-inflammatory cytokine interleukin (IL)-1ß. However, the IL-1ß inhibitors, IL-1 receptor antagonist (IL-1RA) and soluble IL-1 receptor type II (sIL-1RII), regulate IL-1ß bioactivity. In order to better understand the control of IL-1ß activity in the airway mucosa, the role(s) of tumour necrosis factor (TNF)-, cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) in the release of IL-1ß and its inhibitors by cultured HAECs were examined.

HAECs were treated with TNF- (2–200 ng·mL^–1), dibutyryl cAMP (0.01–1 mM), 8-bromo-cGMP (0.01–1 mM) or vehicle for 24 h, and cytokine levels in the HAEC-conditioned medium were measured by enzyme-linked immunosorbent assay.

HAECs produced IL-1ß, IL-1RA and sIL-1RII constitutively, but the inhibitor concentrations greatly exceeded that of IL-1ß (by 100- and 550-fold, respectively). TNF- dose-dependently increased the levels of all IL-1ß cytokine family members. However, over the range of TNF- concentrations studied, IL-1ß concentration increased more than those of its inhibitors. cAMP increased constitutive and TNF--stimulated IL-1ß release but reduced that of sIL-1RII. In contrast, cGMP had no effect on IL-1ß but reduced IL-1RA and sIL-1RII release.

Under basal conditions, the disproportionate release of inhibitors relative to interleukin-1ß by human airway epithelial cells probably prevents interleukin-1ß-mediated biological effects. Tumour necrosis factor-, cyclic adenosine monophosphate and cyclic guanosine monophosphate may potentiate mucosal inflammation by increasing interleukin-1ß levels relative to those of its inhibitors in the airway mucosa.