Intracellular signal cascade in CD4+ T-lymphocyte migration stimulated by interferon-gamma-inducible protein-10.
The intracellular signal cascades involved in chemokine-stimulated migration of in vitro activated human peripheral blood CD4+ T-lymphocytes were investigated. IP-10-mediated chemotactic response of lymphocytes was decreased in the presence of selective inhibitors of Src-kinases (by 40-45%), PI3-kinases (35-40%), and MAP-kinases ERK1/2 (35-40%) and p38 (20%). Combined addition of specific inhibitors of Src-kinases and PI3-kinases and inhibitors of Src-kinases and ERK1/2 MAP-kinases did not result in the further increase of the inhibitory effect, while the combined addition of specific inhibitors of PI3-kinases and ERK1/2 MAP-kinases decreased migration of CD4+ T-lymphocytes more effectively (by 55-60%) than any individual inhibitor. Immunoblotting analysis of activation of MAP-kinases ERK1/2 and p38 revealed increased level of phosphorylation of ERK1/2 and p38 MAP-kinases in the presence IP-10. Selective inhibitors of Src-kinases and PI3-kinases significantly inhibited phosphorylation of p38 but did not influence phosphorylation of ERK1/2 MAP-kinases. Our results suggest that Src-kinases, PI3-kinases, and ERK1/2 MAP-kinases are involved in intracellular signal cascade activated during IP-10-stimulated migration of T-lymphocytes, whereas p38 MAP-kinases do not participate in the migration process, although its activation induced by IP-10 depends on Src-kinases and PI3-kinases.
Kukhtina
N B
NB
Group of Neurobiology of Cardiovascular Diseases, Institute of Experimental Cardiology, Russian Cardiology Research Center, 3-ya Cherepkovskaya ul. 15a, 121552 Moscow, Russia. kukhtina@cardio.ru
Arefieva
T I
TI
Krasnikova
T L
TL
D015496:CD4-Positive T-Lymphocytes / Q000166:cytology*; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D029563:Cellular Apoptosis Susceptibility Protein / Q000032:analysis; D054357:Chemokine CXCL10; D019743:Chemokines, CXC / Q000494:pharmacology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors; D006801:Humans; D008213:Lymphocyte Activation; D020935:MAP Kinase Signaling System / Q000276:immunology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D015398:Signal Transduction / Q000276:immunology*; D019061:src-Family Kinases / Q000037:antagonists & inhibitors
D029563:Cellular Apoptosis Susceptibility Protein; D054357:Chemokine CXCL10; D019743:Chemokines, CXC; D000081082:Phosphoinositide-3 Kinase Inhibitors; D019061:src-Family Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048049:Extracellular Signal-Regulated MAP Kinases