REGULATION OF MONOCYTE INTEGRIN EXPRESSION BY BETA-FAMILY CHEMOKINES

In the present study we investigated the ability of three monocyte che mokines (MCP-1, MIP-1 alpha, and RANTES) to modulate monocyte adhesion molecules in an attempt to evaluate their potential to induce tissue infiltration of macrophages in vivo. All three chemokines tested induc ed increased expression of the alpha-chains of two members of beta(2) family of integrins, CD11b and CD11c, and their common beta-chain (CD1 8). They had no effect on CD11a expression. Enhancement of CD11b and C D11c was dose dependent and followed a distinct time course with peak levels at 4 h. Levels declined to reach basal levels by 24 h. In contr ast, IL-1 induced enhancement remained high after 24 h of stimulation. However, the increases caused by chemokines were not mediated by IL-1 as indicated by lack of inhibition by the IL-1R antagonist. Studies o n the mechanism of integrin up-regulation showed that mobilization of cytosolic free calcium is an important signaling event in this respons e and that up-regulation is associated with mobilization from intracel lular pools mediated by microtubules. Enhanced CD11b and CD11e express ion by chemokines was also found to result in enhancement of monocyte binding to endothelial cells. Further studies indicated that monocyte binding to endothelial cells follows similar dose-response kinetics as the up-regulation of integrins and can be partially blocked by Abs to CD11b and CD11c. These results suggest that modulation of the integri n expression by chemokines may facilitate the tissue trafficking of mo nocytes during inflammation.