The intracellular signaling pathways involved in MCP-1-stimulated T cell migration across microvascular endothelium.
The adherence and transmigration of T cells through microvascular endothelium is an essential step for recruitment into inflammatory lesions, although the factors that stimulate the directional migration of T cells have not been fully characterized. In the present study we investigated the capacity of chemokines to induce migration of T cells across dermal microvascular endothelial cell monolayer. The results showed that recombinant MCP-1 significantly induced transendothelial migration of both resting and activated T cells. Maximal induction of migration was observed at a concentration of 10 ng/ml and a 3- to 4-hr incubation period. In contrast, the chemokines IL-8, RANTES, and MIP-1 alpha failed to stimulate T cell migration at doses as high as 100 ng/ml. In studies designed to investigate the intracellular signaling pathways mediating the MCP-1 effect, the results showed that MCP-1 at doses ranging from 10 to 100 ng/ml did not cause an increase in intracellular calcium ions in T cells, even though this chemokine induced rapid calcium mobilization in monocytes. Furthermore, pretreatment of T cells with either bisindolymaleimide HCl, a specific inhibitor of protein kinase C, or genistein, a protein tyrosine kinase inhibitor, significantly decreased the MCP-1-induced transmigration in a dose-dependent manner. In contrast, T cells pretreated with the protein kinase A-specific inhibitor H89 responded normally to MCP-1 stimulation. Finally, T cell transmigration was inhibited by antibodies against CD11a, thereby confirming the importance of beta 2-integrin in the transmigration process.
Cai
J P
JP
Department of Microbiology, University of Miami School of Medicine, Florida 33101, USA.
Hudson
S
S
Ye
M W
MW
Chin
Y H
YH
D002118:Calcium / Q000378:metabolism; D002465:Cell Movement; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000502:physiology*; D054407:Chemokine CCL4; D018946:Chemokine CCL5 / Q000502:physiology; D002634:Chemotaxis, Leukocyte; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology; D004730:Endothelium, Vascular / Q000166:cytology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D016209:Interleukin-8 / Q000502:physiology; D008213:Lymphocyte Activation; D016169:Lymphocyte Function-Associated Antigen-1 / Q000502:physiology; D019402:Macrophage Inflammatory Proteins; D009000:Monocytes / Q000502:physiology; D015846:Monokines / Q000502:physiology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000502:physiology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000502:physiology; D012867:Skin / Q000098:blood supply; D013601:T-Lymphocytes / Q000166:cytology*
D018932:Chemokine CCL2; D054407:Chemokine CCL4; D018946:Chemokine CCL5; D004791:Enzyme Inhibitors; D016209:Interleukin-8; D016169:Lymphocyte Function-Associated Antigen-1; D019402:Macrophage Inflammatory Proteins; D015846:Monokines; D011505:Protein-Tyrosine Kinases; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; D002118:Calcium