TNF-alpha Contributes To The Development Of Asthma By Enhancing IL-23/Th17 And Th2 Immune Responses

Abstract

RATIONALE: TNF-a has been postulated to be a critical mediator contributing to airway inflammation. The purpose of this study is to evaluate the role of TNF-a in the induction of Th17 and Th2 cells related to asthma pathogenesis. METHODS: Wild type and TNF-a knockout (TNF-a-/-) C57BL/6 mice were intranasally sensitized with LPS 0.1 mg plus OVA. To see the relation between TNF-a and associated effector cytokines, we replenished TNFa -/- mice with IL-23 and IL-4 during sensitization period. To assess cellular resources, CD11c+ cells isolated from lung tissue after sensitization were treated with anti-TNF-a Ab. RESULTS: TNF-a deficiency reduced the number of eosinophils and airway hyperresponsiveness (AHR) in murine asthma model. TNF-a-/- mice showed significant reduction in the level of IL-23 and IL-4 levels after sensitization in bronchoalveolar lavage fluid as well as IL-17A, IL-4 levels in CD4+ T cells after challenge compared withWTmice. Supplementation of IL-23 in TNF-a-/- mice resulted in complete restoration of eosinophilic airway inflammation, AHR, and IL-17A and IL-4 expression in CD4+ T cells. In comparison, supplementation of IL-4 restored eosinophils infiltration in part in the absence of TNF-a. Anti-TNF-a Ab treatment after sensitization significantly diminished the population of IL-23p19-secreting CD11c+ cells in lung. CONCLUSIONS: TNF-a plays an important role in the development of airway inflammation by enhancing IL-23/Th17 and Th2 immune responses.