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* The Shraga Segal Department of Microbiology and Immunology and The Cancer Research Center, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel;
Immunology Research Unit Carmel Medical Center and The Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel;
Institute of Pathology, Kaplan Medical Center, Rehovot, Israel; and
Department of Medicine, University of Colorado Denver, Aurora, CO 80045
Inflammation and angiogenesis are pivotal processes in the progression of many diseases, including malignancies. A hypoxic microenvironment often results in a milieu of proinflammatory and proangiogenic cytokines produced by infiltrating cells. We assessed the role of macrophage-derived hypoxia-associated cytokines in promoting inflammation and angiogenesis. Supernatants of macrophages, stimulated under hypoxia with or without an inflammatory stimulus (LPS), promoted angiogenesis when incorporated into Matrigel plugs. However, neutralization of IL-1 in the supernatants, particularly IL-1β, completely abrogated cell infiltration and angiogenesis in Matrigel plugs and reduced vascular endothelial growth factor (VEGF) levels by 85%. Similarly, supernatants from macrophages of IL-1β knockout mice did not induce inflammatory or angiogenic responses. The importance of IL-1 signaling in the host was demonstrated by the dramatic reduction of inflammatory and angiogenic responses in Matrigel plugs that contained macrophage supernatants from control mice which had been implanted in IL-1 receptor type I knockout mice. Myeloid cells infiltrating into Matrigel plugs were of bone marrow origin and represented the major source of IL-1 and other cytokines/chemokines in the plugs. Cells of endothelial lineage were the main source of VEGF and were recruited mainly from neighboring tissues, rather than from the bone marrow. Using the aortic ring sprouting assay, it was shown that in this experimental system, IL-1 does not directly activate endothelial cell migration, proliferation and organization into blood vessel-like structures, but rather activates infiltrating cells to produce endothelial cell activating factors, such as VEGF. Thus, targeting IL-1β has the potential to inhibit angiogenesis in pathological situations and may be of considerable clinical value.
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 R.N.A. and C.A.D. were supported by the United States-Israel Binational Foundation, the Israel Ministry of Health Chief Scientist’s Office, the German-Israeli Deutsche-Israelische Projectkooperation (DIP) Collaborative Program, the Israel Science Foundation founded by the Israel Academy of Sciences and Humanities, and the European Commission research program INFLA-CARE (EC contract 2231J1). E.V. is supported by the Israel Cancer Association and the European Commission research program INFLA-CARE. C.A.D. is supported by National Institutes of Health Grants AI-15614 and CA-04 6934. R.N.A. is an incumbent of the Irving Isaac Sklar Chair in Endocrinology and Cancer. Y.C. is supported by the Pratt Foundation.
2 Y.C. and E.V. contributed equally to this manuscript.
3 Address correspondence and reprint requests to Dr. Ron N. Apte, The Shraga Segal Department of Microbiology and Immunology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel. E-mail address: rapte{at}bgu.ac.il
4 Abbreviations used in this paper: EPC, endothelial precursor cell; BM, bone marrow; EC, endothelial cell; HIF-1
, hypoxia-inducible factor ; IL-1ra, IL-1 receptor antagonist; KO, knockout; MPC, myeloid precursor cell; MVD, microvessel density; PEC, peritoneal exudates cell; VEGF, vascular endothelial growth factor; vWF, von willebrand factor; WT, wild type; CT, control.
5 The online version of this article contains supplemental material.
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