Specific activation of leukocyte beta 2 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 adhesio n to intercellular adhesion molecule-1 that was mediated by Mac-1 (alpha M beta 2) but not lymphocyte function-associated antigen-1 (LFA-1; alpha L be ta 2). 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-1 alpha in Jurkat cells. Differential kinetics fo r activation of Mac-1 (sustained) and LFA-1 (transient) avidity in response to stromal-derived factor-let were confirmed by expression of alpha M or a lpha L in alpha L-deficient Jurkat cells. Moreover, expression of chimeras containing alpha L and alpha M cytoplasmic domain exchanges indicated that a cytoplasmic tails conferred the specific mode of regulation. Coexpressing alpha M or chimeras in mutant Jurkat cells with a "gain of function" pheno type that results in constitutively active LFA-1 demonstrated that Mac-1 wa s not constitutively active, whereas constitutive activity was mediated via the alpha L cytoplasmic tail, implying the presence of distinct signaling pathways for LFA-1 and Mac-1. Transendothelial chemotaxis of monocytes in r esponse to MCP-1 was dependent on LFA-1; however, Mac-1 was involved at MCP -1 concentrations stimulating its avidity, showing differential contributio ns of beta 2 integrins. Our data suggest that a specific regulation of beta 2 integrin avidity by chemokines may be important in leukocyte extravasati on and may be triggered by distinct activation pathways transduced via the alpha subunit cytoplasmic domains.