Role of adhesion molecules and chemokines in TNF-alpha-induced leukocyte recruitment

Migration of leukocytes from the circulating blood into the extravascular tissue is a key component in inflammatory reactions. Leukocyte extravasation (rolling-activation-adhesion-transmigration) is strictly coordinated by adhesion molecules and chemokines expressed on cell surfaces and in tissues. Tumor necrosis factor-alpha (TNF-alpha) is pleiotrophic cytokine, which plays an important role in the pathophysiology of numerous clinical conditions, including sepsis, rheumatic arthritis and inflammatory bowel diseases. The purpose of this study was to define adhesive pathways and chemokine networks regulating TNF-alpha-induced leukocyte recruitment in vivo. It was found that TNF-alpha-induced leukocyte rolling was mainly mediated by P-selectin. This P-selectin-supported rolling was found to be a precondition for the subsequent firm adhesion and tissue accumulation of leukocytes in response to TNF-alpha. Moreover, by use gene-deficient mice, it was observed that CD18 (Beta2-integrins) is dominating adhesion molecule on leukocytes mediating TNF-alpha-induced leukocyte adhesion. Moreover, it was found that the CXC chemokines, MIP-2 and KC, induced all steps in the extravasation process of leukocytes. In fact, CXC chemokine-induced leukocyte rolling was exclusively dependent on P-selectin, an event, which also was a prerequisite for later firm adhesion and transmigration. CXCR2, which the main receptor for MIP-2 and KC, was not expressed on endothelial cells, suggesting that an intermediary cell(s) mediates CXC chemokine upregulation of P-selectin. TNF-alpha increased gene expression of both MIP-2 and KC. However, no synergistic interaction between MIP-2 and KC was found and immunoneutralization of either MIP-2 or KC had no effect on TNF-alpha-provoked leukocyte responses. On the other hand, inhibition of both MIP-2 and KC markedly reduced tissue migration of leukocyte in response to TNF-alpha. The immunomodulator Linomide was found to inhibit TNF-alpha-induced leukocyte adhesion and accumulation. Taken together, this study demonstrates that leukocyte rolling supported by P-selectin is a common and final pathway for cytokine- and chemokine-induced leukocyte recruitment. Moreover, our data suggest that CXC chemokines are functionally redundant in TNF-alpha-induced accumulation of leukocytes.