Identification and characterization of a monocyte-derived neutrophil-activating factor in corticosteroid-resistant bronchial asthma.

Abstract

Peripheral blood mononuclear cells (PBMC) were isolated from seven normal subjects, eight asthmatic subjects clinically sensitive to corticosteroids (CS), and eight asthmatic subjects clinically resistant to corticosteroids (CR). PBMC were cultured at 370C for 24 h in the absence or presence of 10-16 to i0-' M hydrocortisone. Calcium ionophore (A23187)-activated neutrophils (PMN) primed by supernatants of PBMC from asthmatic subjects cultured in the absence of hydrocortisone generated approximately threefold more leukotriene B4 than PMN primed by supernatants of PBMC from normal subjects (P < 0.05). Incubation of PBMC derived from CS subjects with 10-8 M hydrocortisone completely inhibited the production of the enhancing activity (P < 0.01), whereas in CR subjects hydrocortisone at concentrations up to i0-M did not suppress the release of enhancing activity. The enhancing activity was produced by monocytes. Enhancing activity eluted with an Mr of 3,000 D and a pI of 7.1. It eluted at 10% acetonitrile after reverse-phase HPLC. The activity was destroyed by heating to 60°C for 60 min and was sensitive to pronase treatment. The purified factor also enhanced superoxide generation by PMN which had been stimulated submaximally by phorbol myristate acetate.

Relative Corticosteroid Insensitivity of Peripheral Blood Mononuclear Cells in Severe Asthma

“…The lack of inhibition of a monocyte-derived neutrophil activating factor and of cytokines such as TNF-␣, IL-1␤, and GM-CSF from blood monocytes by corticosteroids of patients with corticosteroid-resistant asthma as compared with patients with corticosteroid-sensitive asthma has been described (7,8). TNF-␣-induced GM-CSF release from PBMCs was also found to be less suppressible by exogenous dexamethasone in a group of patients with corticosteroid-resistant and corticosteroid-dependent asthma (9).…”

Expression of Adhesion Molecules in Cultured Human Nasal Mucosal Microvascular Endothelial Cells Activated by Interleukin–1â or Tumor Necrosis Factor–·: Effects of Dexamethasone

“…Treatment with topical steroids has been shown to inhibit the release of mediators and the influx of inflammatory cells during nasal allergic responses [17, 18, 19]. In addition, steroids cause a significant reduction in the neutrophil infiltration in nonallergic inflammatory respiratory diseases [20, 21]. However, the mechanism of action of steroids on the expression of adhesion molecules is still unclear.…”

Reaction of Mononuclear Cells From Patients with Bronchial Asthma to Candida albicans.

“…The nature of the cellular defect in these CS-resistant individuals is thought to be the monocytes. Recent reports indicate that monocytes, from CS-dependent bronchial asthma patients, secrete a neutrophil-activating factor which is identified in the supernatant of mononuclear cells (Wilkinson et al 1989). Experiments to examine the differences in inhibition of elaboration of cytokines due to the direct effects of steroid hormones on monocytes, or to secondary effects following the interaction of lymphocytes and monocytes are currently underway.…”