Angiogenesis and inflammation are closely related biologic processes in wound healing and the responses to vascular injury as well as in cardiovascular diseases; however, the molecular connections are poorly defined. In particular, it is yet unclear whether endogenous factors can regulate both angiogenesis and inflammation. Here, we show that the endogenous angiogenesis inhibitor, angiostatin (containing kringle domains 1-4 of plasminogen), serves an anti-inflammatory role, since the kringles 1-3 and its kringle 4 directly interact with leukocyte beta1- and beta2-integrins, respectively. In particular, a specific interaction between kringle 4 and alphaMbeta2-integrin (Mac-1) but not leukocyte function antigen 1 (LFA-1) was identified. Angiostatin thereby inhibited beta1- and beta2-integrin-mediated adhesion of leukocytes to extracellular matrix proteins and the endothelium as well as their transmigration through the endothelium in vitro. Moreover, angiostatin blocked the peritonitis-induced neutrophil emigration in vivo. In addition, through its interaction with Mac-1, angiostatin reduced activation of the proinflammatory transcription factor nuclear factor kappaB (NFkappaB), as well as the NFkappaB-related expression of tissue factor, a potent initiator of hemostasis following vascular injury. Finally, angiostatin forms were generated in vivo following skin injury/inflammation and were detectable during the following entire period of wound healing peaking at the terminal phase of the healing process. Taken together, over and above inhibition of neovascularization, angiostatin was identified as an antiadhesive/anti-inflammatory substance. These observations could provide the basis for new therapeutic applications of angiostatin to target chronic inflammatory processes in different pathologic situations.