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Emerging evidence suggests a role of the cytokine midkine (MK) in inflammation. In this study, its functional relevance for recruitment of polymorphonuclear neutrophils (PMNs) during acute inflammation was investigated. Intravital microscopy and histologic analysis of tumor necrosis factor-α-stimulated cremaster muscle venules revealed severely compromised leukocyte adhesion and extravasation in MK^−/− mice compared with MK^+/+ animals. Systemic administration of recombinant MK completely rescued the adhesion defect in MK^−/− mice. In a hind limb ischemia model, leukocyte accumulation in MK^−/− mice was significantly diminished compared with MK^+/+ animals. However, MK did not lead to an inflammatory activation of PMNs or endothelial cells suggesting that it does not serve as classical proinflammatory cytokine. Unexpectedly, immobilized MK mediated PMN adhesion under static and flow …