Differential regulation of chemoattractant-stimulated beta 2, beta 3, and beta 7 integrin activity.
Leukocyte adhesion to endothelium and extravasation are dynamic processes that require activation of integrins. Chemoattractants such as IL-8 and FMLP are potent activators of leukocyte integrins. To compare the chemoattractant-stimulated activation of three integrins, alpha 4 beta 7, alpha L beta 2, and alpha V beta 3, in the same cellular context, we expressed an IL-8 receptor (IL-8RA) and FMLP receptor (FPR) in the lymphoid cell line JY. Chemoattractants induced a rapid increase in alpha L beta 2- and alpha V beta 3-dependent JY adhesion within 5 min, and it was sustained for 30 min. In contrast, stimulation of alpha 4 beta 7-dependent adhesion was transient, returning to basal levels by 30 min. The activation profiles of the integrins were similar regardless of whether IL-8 or FMLP was used for induction. We also demonstrate that alpha 4 beta 7-dependent adhesion was uniquely responsive to the F actin-disrupting agent cytochalasin D and the protein kinase C (PKC) inhibitor chelerythrin. While alpha V beta 3- and alpha L beta 2-mediated cell adhesion was significantly reduced by cytochalasin D, alpha 4 beta 7-mediated adhesion was enhanced. Chelerythrin inhibited both the IL-8 and PMA activation of alpha L beta 2 and alpha V beta 3. In contrast, inducible alpha 4 beta 7 activity was unaffected, and basal activity was increased. These findings demonstrate that the mechanism of alpha 4 beta 7 regulation by chemoattractants is different from that of alpha L beta 2 and alpha V beta 3 and that it appears to involve distinct cytoskeletal and PKC dependencies. In addition, PKC activity may be a positive or negative regulator of integrin-dependent adhesion.
Sadhu
C
C
ICOS Corporation, Bothell, WA 98021, USA.
Masinovsky
B
B
Staunton
D E
DE
D015703:Antigens, CD / Q000096:biosynthesis; D001402:B-Lymphocytes; D002448:Cell Adhesion / Q000187:drug effects; D002461:Cell Line, Transformed; D015638:Cytochalasin D / Q000494:pharmacology; D006801:Humans; D016023:Integrins / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D016209:Interleukin-8 / Q000378:metabolism / Q000494:pharmacology*; D016169:Lymphocyte Function-Associated Antigen-1 / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000378:metabolism / Q000494:pharmacology*; D011493:Protein Kinase C / Q000502:physiology; D044042:Receptors, Formyl Peptide; D011971:Receptors, Immunologic / Q000096:biosynthesis; D018123:Receptors, Interleukin / Q000096:biosynthesis; D023062:Receptors, Interleukin-8A; D018000:Receptors, Peptide / Q000096:biosynthesis; D019030:Receptors, Vitronectin / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D014162:Transfection / Q000276:immunology
D015703:Antigens, CD; D016023:Integrins; D016209:Interleukin-8; D016169:Lymphocyte Function-Associated Antigen-1; D044042:Receptors, Formyl Peptide; D011971:Receptors, Immunologic; D018123:Receptors, Interleukin; D023062:Receptors, Interleukin-8A; D018000:Receptors, Peptide; D019030:Receptors, Vitronectin; C071777:integrin alpha4beta7; D015638:Cytochalasin D; D009240:N-Formylmethionine Leucyl-Phenylalanine; D011493:Protein Kinase C