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Vascular Endothelial Growth Factor Is a Key Mediator in the Development of T Cell Priming and Its Polarization to Type 1 and Type 17 T Helper Cells in the Airways¹

You-Sun Kim,^* Sung-Wook Hong,^* Jun-Pyo Choi,^* Tae-Seop Shin,^* Hyung-Geun Moon,^* Eun-Jung Choi,^* Seong Gyu Jeon,^* Sun-Young Oh, Yong Song Gho,^* Zhou Zhu,² and Yoon-Keun Kim^2*

^*Department of Life Science, POSTECH Biotech Center, Pohang University of Science and Technology (POSTECH), Pohang, Republic of Korea; and Division of Allergy and Clinical Immunology, Asthma and Allergy Center, Johns Hopkins University, Baltimore, MD 21224

Chronic inflammatory airway diseases including asthma are characterized by immune dysfunction to inhaled allergens. Our previous studies demonstrated that T cell priming to inhaled allergens requires LPS, which is ubiquitously present in household dust allergens. In this study, we evaluated the role of vascular endothelial growth factor (VEGF) in the development of T cell priming and its polarization to Th1 or Th17 cells when exposed to LPS-contaminated allergens. An asthma mouse model was induced by airway sensitization with LPS-contaminated allergens and then challenged with allergens alone. Therapeutic intervention was performed during allergen sensitization. The present study showed that lung inflammation induced by sensitization with LPS-contaminated allergens was decreased in mice with homozygous disruption of the IL-17 gene; in addition, allergen-specific Th17 immune response was abolished in IL-6 knockout mice. Meanwhile, in vivo production of VEGF was up-regulated by airway exposure of LPS. In addition, airway sensitization of allergen plus recombinant VEGF induced both type 1 and type 17 Th cell (Th1 and Th17) responses. Th1 and Th17 responses induced by airway sensitization with LPS-contaminated allergens were blocked by treatment with a pan-VEGF receptor (VEGFR; VEGFR-1 plus VEGFR-2) inhibitor during sensitization. These effects were accompanied by inhibition of the production of Th1 and Th17 polarizing cytokines, IL-12p70 and IL-6, respectively. These findings indicate that VEGF produced by LPS plays a key role in activation of naive T cells and subsequent polarization to Th1 and Th17 cells.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This study was supported by grants from the Korea Ministry of Health and Welfare, Republic of Korea (03-PJ10-PG13-GD01-0002, A050193, A050288, and A080711), and the Korea Science and Education Foundation (R01-2007-000-11026-0) to Y.K.K. and by National Institutes of Health Grant HL079349 to Z.Z.

² Address correspondence and reprint requests to: Yoon-Keun Kim, Pohang University of Science and Technology, San 31, Hyojadong, Namgu, Pohang, South Korea or Zhou Zhu, Asthma and Allergy Center, Johns Hopkins University, Baltimore, MD 21224. E-mail addresses: juinea{at}postech.ac.kr and zzhu{at}jhmi.edu

³ Abbreviations used in this paper: VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor; KO, knockout; rVEGF, recombinant VEGF; BAL, bronchoalveolar lavage; DC, dendritic cell; LN, lymph node; IP-10, IFN--inducible protein-10; WT, wild type.