title: Transgenic overexpression of interleukin-1β induces persistent lymphangiogenesis but not angiogenesis in mouse airways.
abstract: These studies used bi-transgenic Clara cell secretory protein (CCSP)/IL-1β mice that conditionally overexpress IL-1β in Clara cells to determine whether IL-1β can promote angiogenesis and lymphangiogenesis in airways. Doxycycline treatment induced rapid, abundant, and reversible IL-1β production, influx of neutrophils and macrophages, and conspicuous and persistent lymphangiogenesis, but surprisingly no angiogenesis. Gene profiling showed many up-regulated genes, including chemokines (Cxcl1, Ccl7), cytokines (tumor necrosis factor α, IL-1β, and lymphotoxin-β), and leukocyte genes (S100A9, Aif1/Iba1). Newly formed lymphatics persisted after IL-1β overexpression was stopped. Further studies examined how IL1R1 receptor activation by IL-1β induced lymphangiogenesis. Inactivation of vascular endothelial growth factor (VEGF)-C and VEGF-D by adeno-associated viral vector-mediated soluble VEGFR-3 (VEGF-C/D Trap) completely blocked lymphangiogenesis, showing its dependence on VEGFR-3 ligands. Consistent with this mechanism, VEGF-C immunoreactivity was present in some Aif1/Iba1-immunoreactive macrophages. Because neutrophils contribute to IL-1β-induced lung remodeling in newborn mice, we examined their potential role in lymphangiogenesis. Triple-transgenic CCSP/IL-1β/CXCR2(-/-) mice had the usual IL-1β-mediated lymphangiogenesis but no neutrophil recruitment, suggesting that neutrophils are not essential. IL1R1 immunoreactivity was found on some epithelial basal cells and neuroendocrine cells, suggesting that these cells are targets of IL-1β, but was not detected on lymphatics, blood vessels, or leukocytes. We conclude that lymphangiogenesis triggered by IL-1β overexpression in mouse airways is driven by VEGF-C/D from macrophages, but not neutrophils, recruited by chemokines from epithelial cells that express IL1R1.
authors: Cardiovascular Research Institute, University of California, San Francisco, California 94143-0130, USA. peter.baluk@ucsf.edu
authors: Peter
authors: P
authors: Baluk
authors: Anna
authors: A
authors: Hogmalm
authors: Maija
authors: M
authors: Bry
authors: Kari
authors: K
authors: Alitalo
authors: Kristina
authors: K
authors: Bry
authors: Donald M
authors: DM
authors: McDonald
mesh_terms: D000818:Animals; D001808:Blood Vessels / Q000378:metabolism / Q000473:pathology; D004848:Epithelium / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation; D006801:Humans; D006984:Hypertrophy; D053583:Interleukin-1beta / Q000378:metabolism*; D042583:Lymphangiogenesis / Q000235:genetics; D042601:Lymphatic Vessels / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D009504:Neutrophils / Q000378:metabolism / Q000473:pathology; D021381:Protein Transport; D017472:Receptors, Interleukin-1 / Q000378:metabolism; D023063:Receptors, Interleukin-8B / Q000378:metabolism; D014132:Trachea / Q000098:blood supply* / Q000473:pathology*
chemical_list: D053583:Interleukin-1beta; D017472:Receptors, Interleukin-1; D023063:Receptors, Interleukin-8B
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