Guanylate binding protein-1 inhibits spreading and migration of endothelial cells through induction of integrin α4 expression

被引:61
作者
Weinlaender, Kristina [1 ]
Naschberger, Elisabeth [1 ]
Lehmann, Michael H. [1 ]
Tripal, Philipp [1 ]
Paster, Wolfgang [2 ]
Stockinger, Hannes [2 ]
Hohenadl, Christine [3 ]
Stuerzl, Michael [1 ]
机构
[1] Univ Erlangen Nurnberg, Div Mol & Expt Surg, Dept Surg, D-91054 Erlangen, Germany
[2] Med Univ Vienna, Dept Mol Immunol, Ctr Physiol Pathophysiol & Immunol, Vienna, Austria
[3] Univ Vet Med, Dept Pathobiol, Inst Virol, Vienna, Austria
关键词
angiogenesis; inflammation; integrins; large GTPase;
D O I
10.1096/fj.08-107524
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Human guanylate binding protein-1 (GBP-1) is a large GTPase that is induced by inflammatory cytokines and acts antiangiogenically through the inhibition of endothelial cell proliferation and migration. In this study, we detected that GBP-1-expressing cells show a significantly reduced spreading and migration on fibronectin matrices. Investigating possible mechanisms of these effects, we found that integrin alpha(4) (ITGA4) was consistently up-regulated at both the RNA and protein level in GBP-1-expressing cell cultures. Inhibition of cell spreading and migration by GBP-1 was dependent on the binding of ITGA4 to fibronectin. The inflammatory cytokines IL-1 beta and TNF-alpha induced ITGA4 expression in HUVECs and inhibited spreading and migration. Knockdown of GBP-1 by shRNA abrogated inflammatory cytokine induced ITGA4 expression and restored spreading and migration capabilities of the cells. These results show that inhibition of endothelial cell spreading and migration by inflammatory cytokines is mediated by GBP-1 through induction of ITGA4 expression. Endothelial cell migration is a key process during angiogenesis. Therefore, ITGA4 may be a novel molecular target to modulate angiogenesis in human disease.
引用
收藏
页码:4168 / 4178
页数:11
相关论文
共 75 条
[1]   CDNA STRUCTURES AND REGULATION OF 2 INTERFERON-INDUCED HUMAN MX PROTEINS [J].
AEBI, M ;
FAH, J ;
HURT, N ;
SAMUEL, CE ;
THOMIS, D ;
BAZZIGHER, L ;
PAVLOVIC, J ;
HALLER, O ;
STAEHELI, P .
MOLECULAR AND CELLULAR BIOLOGY, 1989, 9 (11) :5062-5072
[2]   Interferon-induced guanylate binding protein-1 (GBP-1) mediates an antiviral effect against vesicular stomatitis virus and encephalomyocarditis virus [J].
Anderson, SL ;
Carton, JM ;
Lou, J ;
Xing, L ;
Rubin, BY .
VIROLOGY, 1999, 256 (01) :8-14
[3]   Rac GTPase instructs nuclear factor-κB activation by conveying the SCF complex and IκBα to the ruffling membranes [J].
Boyer, L ;
Travaglione, S ;
Falzano, L ;
Gauthier, NC ;
Popoff, MR ;
Lemichez, E ;
Fiorentini, C ;
Fabbri, A .
MOLECULAR BIOLOGY OF THE CELL, 2004, 15 (03) :1124-1133
[4]   β1 integrin function in vivo:: Adhesion, migration and more [J].
Brakebusch, C ;
Fässler, R .
CANCER AND METASTASIS REVIEWS, 2005, 24 (03) :403-411
[5]  
Brezinschek RI, 1996, AM J PATHOL, V149, P1651
[6]   VEGF as a key mediator of angiogenesis in cancer [J].
Carmeliet, P .
ONCOLOGY, 2005, 69 :4-10
[7]   Angiogenesis in cancer and other diseases [J].
Carmeliet, P ;
Jain, RK .
NATURE, 2000, 407 (6801) :249-257
[8]   Inhibition of VSV and EMCV replication by the interferon-induced GTPase, mGBP-2: differential requirement for wild-type GTP binding domain [J].
Carter, CC ;
Gorbacheva, VY ;
Vestal, DJ .
ARCHIVES OF VIROLOGY, 2005, 150 (06) :1213-1220
[9]   DISTINCT CELLULAR FUNCTIONS MEDIATED BY DIFFERENT VLA INTEGRIN ALPHA-SUBUNIT CYTOPLASMIC DOMAINS [J].
CHAN, BM ;
KASSNER, PD ;
SCHIRO, JA ;
BYERS, HR ;
KUPPER, TS ;
HEMLER, ME .
CELL, 1992, 68 (06) :1051-1060
[10]  
CHENG YSE, 1983, J BIOL CHEM, V258, P7746