Inhibitory control of TGF-beta1 on the activation of Rap1, CD11b, and transendothelial migration of leukocytes.
Beta2-integrins are a family of dimeric adhesion molecules expressed on leukocytes. Their capacity to bind ligand is regulated by their state of activation. CD11b, an alphaMbeta2 integrin, is implicated in a number of physiological and pathological events such as inflammation, thrombosis, or atherosclerosis. The GTPase Rap1 is essential for its activation and could therefore play a strategic role in the regulation of leukocyte functioning. Because low levels of circulating TGF-beta have been linked with severe atherosclerosis, we have assessed the role of this cytokine in the regulation of Rap1 and CD11b activation in differentiated U937 cells and in human peripheral blood monocytes. TGF-beta1 caused a significant reduction in the expression of CD11b but not in the expression of other integrins tested. More importantly, TGF-beta1 greatly reduced the capacity of PMA or chemokines to activate CD11b and Rap1, a phenomenon paralleled by a loss of the Epac transcript and a reduction in 8-pCPT-2'-O-Me-cAMP-mediated activation of Rap1. This inhibition diminished the capacity of monocytes to migrate across a monolayer of endothelial cells. The inhibitory effect of TGF-beta1 on Rap1 activity may exert a general protective influence against aberrant transendothelial migration, thereby holding inflammatory responses in check.
Basoni
Caroline
C
U441 INSERM, Pessac, France.
Nobles
Muriel
M
Grimshaw
Andrew
A
Desgranges
Claude
C
Davies
Derek
D
Perretti
Mauro
M
Kramer
Ijsbrand M
IM
Genot
Elisabeth
E
D039481:CD11b Antigen / Q000032:analysis / Q000502:physiology*; D002448:Cell Adhesion; D002454:Cell Differentiation; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology*; D054407:Chemokine CCL4; D042783:Endothelial Cells; D004789:Enzyme Activation / Q000187:drug effects; D005434:Flow Cytometry; D005456:Fluorescent Dyes; D020662:Guanine Nucleotide Exchange Factors / Q000032:analysis / Q000235:genetics; D006801:Humans; D039441:Integrin alpha4 / Q000032:analysis; D016023:Integrins / Q000032:analysis; D007962:Leukocytes / Q000502:physiology*; D018950:Lipopolysaccharide Receptors / Q000032:analysis; D019402:Macrophage Inflammatory Proteins / Q000494:pharmacology; D008297:Male; D009000:Monocytes / Q000502:physiology; D012333:RNA, Messenger / Q000032:analysis; D012395:Rose Bengal; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D053773:Transforming Growth Factor beta1; D020298:U937 Cells; D020827:rap1 GTP-Binding Proteins / Q000235:genetics / Q000502:physiology*
D039481:CD11b Antigen; D054407:Chemokine CCL4; D005456:Fluorescent Dyes; D020662:Guanine Nucleotide Exchange Factors; D016023:Integrins; D018950:Lipopolysaccharide Receptors; D019402:Macrophage Inflammatory Proteins; C116122:RAPGEF3 protein, human; D012333:RNA, Messenger; C508960:TGFB1 protein, human; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D039441:Integrin alpha4; D012395:Rose Bengal; D020827:rap1 GTP-Binding Proteins; D013755:Tetradecanoylphorbol Acetate