Novel Functional Role of inflammatory cytokines, IL- 1beta, IL-6, and TNFalpha in angiogenesis revealed by analysis of their knockout mice

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Background : Endothelial progenitor cells (EPC) have been found to mobilize into adult peripheral blood in response to regional ischemia, and play a critical role in neovascularization in ischemic region. Also VEGF have been found to induce the mobilization of bone marrow derived EPC. Meanwhile we have reported that interleukin-1 beta (IL-1β) up-regulates cardiac expression of vascular endothelial growth factor (VEGF) and VEGF receptor-2, raising the possibility that IL-1β plays a important role in VEGF-mediated neovascularization. In this study, we examined the cellular mechanism for ischemia-induced neovascularization using IL-1β knockout (-/-) mice. Method and Result : 1)Recovery of blood perfusion in ischemic hindlimb in IL-1β-/- mice was markedly (43% decrease) impaired as compared with the wild type mice. CD31+ vessel numbers and Ki-67+ neo-capillaries were significantly (p<0.01) decreased 44% and 68%, respectively. 2)IL-1β expression was localized in the capillary vessels in isc … More hemic limb muscles. Ischemia-induced expression of HIF1α, VEGF and its receptor VEGFR-2 was markedly inhibited in the IL-1β-/-mice. 3)Hindlimb ischemia induced an increase (1.22% out of total nuclear cell) in CD34^-/B220^-/CD3^-/Flk1^+ hematopoietic stem cell population in peripheral blood in the wild type mice, whereas in the IL-1β-/-mice such increase was only 0.09%. 4)Injection of IL-1β protein into the wild-type mice markedly increased the ratio of the CD34^-/B220^-/CD3^-/Flk1^+ cell population (from 0.03 to 0.7%) in the peripheral blood associated with an increase in the number of endothelial cells. Such IL-1β-mediated increases in cell numbers were blocked by co-injection of anti-VEGF antibody. 5)CD34^-/B220^-CD3^-Flk1^+ cells trans-differentiated into eNOS- and CD31-expressing endothelial cells in vitro and in vivo. Conclusion : In this study demonstrates the critical role of inflammatory cytokine IL-1β to enhance neo-capillary formation in limb ischemia. IL-1β-mediated expression of HIF-1α, VEGF and its receptor, or mobilization of CD34-Flk-1+ endothelial precursor cells is closely involved in IL1-β-induced neovascularization. Less