Tumour necrosis factor-alpha: The role of this multifunctional cytokine inasthma

Tumour necrosis factor-alpha (TNF-alpha) is recognized as an important medi ator In many cytokine-dependent inflammatory events. It is known that TNF-a lpha Is released in allergic responses from both mast cells and macrophages cia IgE-dependent mechanisms, and elevated levels have been demonstrated i n the bronchoalveolar fluid(BALF) of asthmatic subjects undergoing allergen challenge. Inhaled TNF-alpha increases airway responsiveness to methacholi ne in normal and asthmatic subjects associated with ha sputum neutrophilia. Additional data indicate that TNF-alpha can upregulate adhesion molecules, facilitate the immigration of Inflammatory cells into the airway wall and activate pro-fibrotic mechanisms in the subepithelium. These data suggest t hat TNF-alpha plays a role in the initiation of allergic asthmatic airway i nflammation and the generation of airway hyper-reactivity. In addition, pol ymorphisms of the TNF-alpha gene 5' untranslated region, particularly at -3 08 bp, have been described as being associated with asthma. This polymorphi sm is associated with increased levels of TNF-alpha, but as yet, no asthma studies have demonstrated a phenotypic difference between those individuals with the polymorphism and those with the wild type gene. The TNF receptors (TNF-R p55 and p75), also known as CD120a and b, have also been shown to b e present in the lung, but their functional importance is only lust emergin g. In asthma, TNF may function as a pro-inflammatory cytokine that causes t he recruitment of neutrophils and eosinophils. Treatment directed specifica lly at a reduction in TNF-alpha activity may conceivably be useful as a glu cocorticosteroid-sparing asthma therapy.