The role of vascular endothelial growth factor (VEGF) in the development of T cell priming to inhaled allergens and its polarization to type 17 T helper (Th17) cells when exposed to lipopolysaccharide

다국어 초록 (Multilingual Abstract)

Asthma is characterized by T cell priming rather than tolerance to inhaled innocuous antigens(allergens) which results in chronic inflammation in the airways. Lipopolysaccharide(LPS) is ubiquitously present in the household dust allergens; our previous studies demonstrate that T cell priming to inhaled allergens requires LPS. Previous transgenic studies indicate that high levels of VEGF in the airways enhance T cell priming to inhaled allergens. Our present studies showed that in vivo production of VEGF was up-regulated by airway exposure of LPS; moreover, airway sensitization of an allergen plus recombinant VEGF enhanced T cell priming and Th17 immune response to inhaled allergens. Meanwhile, airway sensitization with an allergen and LPS induced Th1 and Th17 immune responses to inhaled allergens; these immune responses was blocked by treatment of a pan-VEGFR(VEGFR-1 + VEGFR-2) inhibitor during sensitization. Interestingly, treatment of a specific VEGFR-1 inhibitor during sensitization reduced expression of co-stimulatory molecules on lung dendritic cells enhanced by LPS, which resulted in T cell tolerance to allergens. In vivo studies showed that Th17 immune response induced by LPS-contaminated allergens was completely blocked in the absence of IL-6; moreover, the treatment of a specific VEGFR-2 inhibitor during sensitization abolished IL-6 production enhanced by LPS and allergen-specific Th17 immune response. Taken together, these findings indicate that VEGF produced by LPS plays a key role in the development of T cell priming to inhalant allergens, mainly via up-regulation of expression of co-stimulatory molecules by VEGFR-I signaling, and Th17 polarization, mainly via up-regulation of IL-6 production by VEGFR-2 signaling.