Specific activation of leukocyte beta2 integrins lymphocyte function-associated antigen-1 and Mac-1 by chemokines mediated by distinct pathways via the alpha subunit cytoplasmic domains.
We show that CC chemokines induced a sustained increase in monocyte adhesion to intercellular adhesion molecule-1 that was mediated by Mac-1 (alphaMbeta2) but not lymphocyte function-associated antigen-1 (LFA-1; alphaLbeta2). In contrast, staining for an activation epitope revealed a rapid and transient up-regulation of LFA-1 activity by monocyte chemotactic protein-1 (MCP-1) in monocytes and Jurkat CCR2 chemokine receptor transfectants or by stromal-derived factor-1alpha in Jurkat cells. Differential kinetics for activation of Mac-1 (sustained) and LFA-1 (transient) avidity in response to stromal-derived factor-1alpha were confirmed by expression of alphaM or alphaL in alphaL-deficient Jurkat cells. Moreover, expression of chimeras containing alphaL and alphaM cytoplasmic domain exchanges indicated that alpha cytoplasmic tails conferred the specific mode of regulation. Coexpressing alphaM or chimeras in mutant Jurkat cells with a "gain of function" phenotype that results in constitutively active LFA-1 demonstrated that Mac-1 was not constitutively active, whereas constitutive activity was mediated via the alphaL cytoplasmic tail, implying the presence of distinct signaling pathways for LFA-1 and Mac-1. Transendothelial chemotaxis of monocytes in response to MCP-1 was dependent on LFA-1; however, Mac-1 was involved at MCP-1 concentrations stimulating its avidity, showing differential contributions of beta2 integrins. Our data suggest that a specific regulation of beta2 integrin avidity by chemokines may be important in leukocyte extravasation and may be triggered by distinct activation pathways transduced via the alpha subunit cytoplasmic domains.
Weber
K S
KS
Institut für Prophylaxe der Kreislaufkrankheiten, Ludwig-Maximilians-Universität, D-80336 München, Germany.
Klickstein
L B
LB
Weber
C
C
D018821:CD18 Antigens / Q000502:physiology*; D002448:Cell Adhesion; D018932:Chemokine CCL2 / Q000494:pharmacology; D054407:Chemokine CCL4; D018946:Chemokine CCL5 / Q000494:pharmacology; D003593:Cytoplasm / Q000502:physiology; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D019169:Jurkat Cells; D016169:Lymphocyte Function-Associated Antigen-1 / Q000235:genetics / Q000502:physiology*; D019402:Macrophage Inflammatory Proteins / Q000494:pharmacology; D016177:Macrophage-1 Antigen / Q000502:physiology*; D054390:Receptors, CCR2; D019707:Receptors, Chemokine / Q000502:physiology; D018121:Receptors, Cytokine / Q000235:genetics / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D011994:Recombinant Proteins / Q000378:metabolism / Q000494:pharmacology; D013601:T-Lymphocytes / Q000276:immunology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014162:Transfection
C515334:CCR2 protein, human; D018821:CD18 Antigens; D018932:Chemokine CCL2; D054407:Chemokine CCL4; D018946:Chemokine CCL5; D016169:Lymphocyte Function-Associated Antigen-1; D019402:Macrophage Inflammatory Proteins; D016177:Macrophage-1 Antigen; D054390:Receptors, CCR2; D019707:Receptors, Chemokine; D018121:Receptors, Cytokine; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; D013755:Tetradecanoylphorbol Acetate