Fluticasone induces T cell apoptosis in the bronchial wall of mild to moderate asthmatics

Apoptosis has emerged as a major mechanism for the clearance of activated T cells during the resolution of an inflammatory response. ¹ It has been proposed that dysregulation of the survival and apoptosis of inflammatory cells has a central role in chronic inflammation. ^{2- 4}

Activated T cell apoptosis can occur via two distinct pathways: activation induced cell death involves ligation between FAS and its ligand ⁵ while cytokine deprivation death of activated T cells tends to occur at the end of the immune response. ⁶ Withdrawal of cytokines-specifically those which signal via the [GAMMA]-chain of the interleukin (IL)-2 receptor (IL-2R), IL-2, IL-4, IL-7 and IL-15-leads to apoptosis associated with the downregulation of the anti-apoptotic molecule Bcl-2. ⁷ Deprivation of a second group of cytokines, the type I interferons (IFNs), also results in T cell apoptosis, ⁸ but Bcl-2 expression does not appear to be central to this process. ⁹

Compelling evidence has recently accumulated which attests to a defect in the regulation of apoptosis in asthma. ^{10- 12} Asthma is characterised by a chronic inflammation of the bronchial wall dominated by T lymphocytes and eosinophils. ¹³ The accumulation of these cells in the asthmatic airway significantly contributes to the persistence of airway inflammation in these patients. Wolley et al have found decreased numbers of eosinophils undergoing apoptosis in asthmatic subjects compared with a non-asthmatic control group. ¹⁴ In addition, eosinophil expression of the anti-apoptotic gene product Bcl-2 is increased in bronchial biopsy material from asthmatic subjects. ¹¹ The role of T cell apoptosis has only recently received any attention. Spinozzi et al recently reported hypoexpression of FAS mRNA and its receptor FAS ligand, two molecules necessary for activation induced cell death, by pulmonary T cells isolated from bronchoalveolar lavage (BAL) fluid of subjects with atopic asthma. ¹⁵

Previous observations from our laboratory have shown a reduction in the expression of Bcl-2 by the CD4+ T cell population in asthmatic subjects compared with a non-asthmatic control group. ¹⁶ Furthermore, IFN-[GAMMA] positive but not IL-4 positive T cells in biopsy specimens from asthmatic subjects had significantly higher proportions of apoptotic cells, supporting the hypothesis that a Th1/Th2 imbalance in asthmatic inflammation may be a result of premature apoptosis within the Th1 subset. ¹⁶

Corticosteroids constitute first...