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Transgenic overexpression of interleukin-1? induces persistent lymphangiogenesis but not angiogenesis in mouse airways.

ABSTRACT: These studies used bi-transgenic Clara cell secretory protein (CCSP)/IL-1? mice that conditionally overexpress IL-1? in Clara cells to determine whether IL-1? can promote angiogenesis and lymphangiogenesis in airways. Doxycycline treatment induced rapid, abundant, and reversible IL-1? 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 ?, IL-1?, and lymphotoxin-?), and leukocyte genes (S100A9, Aif1/Iba1). Newly formed lymphatics persisted after IL-1? overexpression was stopped. Further studies examined how IL1R1 receptor activation by IL-1? 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-1?-induced lung remodeling in newborn mice, we examined their potential role in lymphangiogenesis. Triple-transgenic CCSP/IL-1?/CXCR2(-/-) mice had the usual IL-1?-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-1?, but was not detected on lymphatics, blood vessels, or leukocytes. We conclude that lymphangiogenesis triggered by IL-1? overexpression in mouse airways is driven by VEGF-C/D from macrophages, but not neutrophils, recruited by chemokines from epithelial cells that express IL1R1.

SUBMITTER: Baluk P

PROVIDER: S-EPMC3620402 | biostudies-literature | 2013 Apr

REPOSITORIES: biostudies-literature

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Transgenic overexpression of interleukin-1β induces persistent lymphangiogenesis but not angiogenesis in mouse airways.

Baluk Peter P Hogmalm Anna A Bry Maija M Alitalo Kari K Bry Kristina K McDonald Donald M DM

The American journal of pathology 20130204 4

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, Ccl ...[more]

PMID: 23391392

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Project description:The formation of new blood vessels (angiogenesis) is required for the growth of most tumors. The tumor microenvironment also induces lymphangiogenic factors that promote metastatic spread. Anti-angiogenic therapy targets the mechanisms behind the growth of the tumor vasculature. During the past two decades, several strategies targeting blood and lymphatic vessels in tumors have been developed. The blocking of vascular endothelial growth factor (VEGF)/VEGF receptor-2 (VEGFR-2) signaling has proven effective for inhibition of tumor angiogenesis and growth, and inhibitors of VEGF-C/VEGFR-3 involved in lymphangiogenesis have recently entered clinical trials. However, thus far anti-angiogenic treatments have been less effective in humans than predicted on the basis of pre-clinical tests in mice. Intrinsic and induced resistance against anti-angiogenesis occurs in patients, and thus far the clinical benefit of the treatments has been limited to modest improvements in overall survival in selected tumor types. Our current knowledge of tumor angiogenesis is based mainly on experiments performed in tumor-transplanted mice, and it has become evident that these models are not representative of human cancer. For an improved understanding, angiogenesis research needs models that better recapitulate the multistep tumorigenesis of human cancers, from the initial genetic insults in single cells to malignant progression in a proper tissue environment. To improve anti-angiogenic therapies in cancer patients, it is necessary to identify additional molecular targets important for tumor angiogenesis, and to get mechanistic insight into their interactions for eventual combinatorial targeting. The recent development of techniques for manipulating the mammalian genome in a precise and predictable manner has opened up new possibilities for the generation of more reliable models of human cancer that are essential for the testing of new therapeutic strategies. In addition, new imaging modalities that permit visualization of the entire mouse tumor vasculature down to the resolution of single capillaries have been developed in pre-clinical models and will likely benefit clinical imaging.

Dataset Information

Transgenic overexpression of interleukin-1? induces persistent lymphangiogenesis but not angiogenesis in mouse airways.

Publications

Transgenic overexpression of interleukin-1β induces persistent lymphangiogenesis but not angiogenesis in mouse airways.

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