Regulation of monocyte integrin expression by beta-family chemokines.
In the present study we investigated the ability of three monocyte chemokines (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 induced increased expression of the alpha-chains of two members of beta 2 family of integrins, CD11b and CD11c, and their common beta-chain (CD18). They had no effect on CD11a expression. Enhancement of CD11b and CD11c 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 contrast, 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 on the mechanism of integrin up-regulation showed that mobilization of cytosolic free calcium is an important signaling event in this response and that up-regulation is associated with mobilization from intracellular pools mediated by microtubules. Enhanced CD11b and CD11c expression 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 integrin expression by chemokines may facilitate the tissue trafficking of monocytes during inflammation.
Vaddi
K
K
Inflammatory Diseases Research, DuPont Merck Pharmaceutical Company, Wilmington, DE 19880.
Newton
R C
RC
D018821:CD18 Antigens; D002118:Calcium / Q000502:physiology; D002448:Cell Adhesion / Q000502:physiology; D002630:Chemotactic Factors / Q000502:physiology*; D016207:Cytokines / Q000502:physiology*; D005434:Flow Cytometry; D019204:GTP-Binding Proteins / Q000502:physiology; D006801:Humans; D066298:In Vitro Techniques; D016023:Integrins / Q000096:biosynthesis*; D007375:Interleukin-1 / Q000502:physiology; D007975:Leukotriene B4 / Q000494:pharmacology; D009000:Monocytes / Q000276:immunology*; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D010972:Platelet Activating Factor / Q000494:pharmacology; D015854:Up-Regulation / Q000502:physiology
D018821:CD18 Antigens; D002630:Chemotactic Factors; D016207:Cytokines; D016023:Integrins; D007375:Interleukin-1; D010972:Platelet Activating Factor; D007975:Leukotriene B4; D009240:N-Formylmethionine Leucyl-Phenylalanine; D019204:GTP-Binding Proteins; D002118:Calcium