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Th1/Th2 Cytokines Reciprocally Regulate In Vitro Pulmonary Angiogenesis via CXC Chemokine Synthesis

¹ Department of Allergy and Immunology, National Research Institute for Child Health and Development, Tokyo, Japan

Correspondence and requests for reprints should be addressed to Akio Matsuda, Ph.D., Department of Allergy and Immunology, National Research Institute for Child Health and Development, 2-10-1 Okura, Setagaya-ku, Tokyo, 157-8535, Japan. E-mail: amatsuda{at}nch.go.jp

Hypervascularity is known as an important element of airway remodeling in bronchial asthma. However, it remains obscure how allergic inflammation relates to angiogenesis in the lung. In this study, we examined the in vitro effects of inflammatory cytokines on endothelial cell functions, particularly angiogenesis. Human microvascular endothelial cells from normal lung (HMVEC-Ls) were cultured with TNF-, IFN-, IL-4, a combination of TNF- and IFN-, or a combination of TNF- and IL-4, and the cell proliferation and tube-forming activities were evaluated. IL-4 slightly enhanced the proliferation of HMVEC-Ls in the presence of vascular endothelial growth factor (VEGF), whereas TNF- and IFN- tended to inhibit it. Synergistic inhibition was observed when TNF- and IFN- were simultaneously added to the culture medium. The combination of IL-4 and TNF- markedly promoted tube formation by HMVEC-Ls, even in the absence of VEGF. The IL-4 and TNF- combination induced autocrine production of CXCR2 chemokines, which are known to have angiogenic activity, whereas the production of angiostatic CXCR3 chemokines was dramatically up-regulated when TNF- and IFN- were present. The marked IL-4– and TNF-–induced tube formation was inhibited by a selective CXCR2 antagonist. These results suggest that, in the presence of TNF-, IL-4 and IFN- reciprocally regulate tube formation by HMVEC-Ls through autocrine synthesis of CXCR2 and CXCR3 chemokines, respectively. Of note, the CXCR2 chemokine-induced tube formation was independent of VEGF. Therefore, CXCR2 chemokines may represent potential therapeutic targets for bronchial asthma.

Key Words: airway remodeling • angiogenesis • CXC chemokine • cytokine • Th1/Th2

CLINICAL RELEVANCE Our findings revealed that autocrine CXCR2 chemokines are indispensable for lung angiogenesis, and might shed new light on the potential of CXCR2 as a novel therapeutic target for airway hypervascularity, particularly in patients with severe asthma.