Permeabilization in a cerebral endothelial barrier model by pertussis toxin involves the PKC effector pathway and is abolished by elevated levels of cAMP

被引:54
作者
Brückener, KE
el Bayâ, A
Galla, HJ
Schmidt, MA [1 ]
机构
[1] Univ Klinikum, Inst Infektiol, Zentrum Mol Entzundung ZMBE, Munster, Germany
[2] Univ Munster, Inst Biochem, D-48149 Munster, Germany
关键词
cerebral endothelial barriers; pertussis toxin; transient permeabilization; PKC; cAMP;
D O I
10.1242/jcs.00378
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
Respiratory tract infections caused by Bordetella pertussis are occasionally accompanied by severe neurologic disorders and encephalopathies. For these sequelae to occur the integrity of cerebral barriers needs to be compromised. The influence of pertussis toxin, a decisive virulence factor in the pathogenesis of pertussis disease, on barrier integrity was investigated in model systems for blood-liquor (epithelial) and blood-brain (endothelial) barriers. While pertussis toxin did not influence the barrier function in Plexus chorioideus model systems, the integrity of cerebral endothelial monolayers was severely compromised. Cellular intoxication by pertussis toxin proceeds via ADP-ribosylation of alpha-G(i) proteins, which not only interferes with the homeostatic inhibitory regulation of adenylate cyclase stimulation but also results in a modulation of the membrane receptor coupling. Increasing intra-endothelial cAMP levels by employing cholera toxin or forskolin even inhibited the pertussis toxin-induced permeabilization of endothelial barriers. Therefore, pertussis-toxin-induced permeabilization has to be mediated via a cAMP-independent pathway. To investigate potential signalling pathways we employed several well established cellular drugs activating or inhibiting central effectors of signal transduction pathways, such as phosphatidylinositol 3-kinase, adenylate cyclase, phospholipase C, myosin light chain kinase and protein kinase C. Only inhibitors and activators of protein kinase C and phosphatidylinositol 3-kinase affected the pertussis toxin-induced permeability. In summary, we conclude that permeabilization of cerebral endothelial monolayers by pertussis toxin does not depend on elevated cAMP levels and proceeds via the phosphokinase C pathway.
引用
收藏
页码:1837 / 1846
页数:10
相关论文
共 58 条
[41]   PROKARYOTIC PEPTIDES THAT BLOCK LEUKOCYTE ADHERENCE TO SELECTINS [J].
ROZDZINSKI, E ;
BURNETTE, WN ;
JONES, T ;
MAR, V ;
TUOMANEN, E .
JOURNAL OF EXPERIMENTAL MEDICINE, 1993, 178 (03) :917-924
[42]   Phosphatidylinositol 3-OH kinase activity is not required for activation of mitogen-activated protein kinase by cytokines [J].
Scheid, MP ;
Duronio, V .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1996, 271 (30) :18134-18139
[43]   Multiple isoforms of the regulatory subunit for phosphatidylinositol 3-kinase (PI3-kinase) are expressed in neurons in the rat brain [J].
Shin, BC ;
Suzuki, M ;
Inukai, K ;
Anai, M ;
Asano, T ;
Takata, K .
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 1998, 246 (02) :313-319
[44]   PROTEIN-KINASE-C PHOSPHORYLATES CALDESMON77 AND VIMENTIN AND ENHANCES ALBUMIN PERMEABILITY ACROSS CULTURED BOVINE PULMONARY-ARTERY ENDOTHELIAL-CELL MONOLAYERS [J].
STASEK, JE ;
PATTERSON, CE ;
GARCIA, JGN .
JOURNAL OF CELLULAR PHYSIOLOGY, 1992, 153 (01) :62-75
[45]   ROLE OF CYCLIC ADENOSINE-MONOPHOSPHATE IN THE INDUCTION OF ENDOTHELIAL BARRIER PROPERTIES [J].
STELZNER, TJ ;
WEIL, JV ;
OBRIEN, RF .
JOURNAL OF CELLULAR PHYSIOLOGY, 1989, 139 (01) :157-166
[46]   The G beta gamma sensitivity of a PI3K is dependent upon a tightly associated adaptor, p101 [J].
Stephens, LR ;
Eguinoa, A ;
ErdjumentBromage, H ;
Lui, M ;
Cooke, F ;
Coadwell, J ;
Smrcka, AS ;
Thelen, M ;
Cadwallader, K ;
Tempst, P ;
Hawkins, PT .
CELL, 1997, 89 (01) :105-114
[47]   PI 3-kinase γ and protein kinase C-ζ mediate RAS-independent activation of MAP kinase by a Gi protein-coupled receptor [J].
Takeda, H ;
Matozaki, T ;
Takada, T ;
Noguchi, T ;
Yamao, T ;
Tsuda, M ;
Ochi, F ;
Fukunaga, K ;
Inagaki, K ;
Kasuga, M .
EMBO JOURNAL, 1999, 18 (02) :386-395
[48]  
TAMURA M, 1983, J BIOL CHEM, V258, P6756
[49]  
Tewes B, 1997, DRUG TRANSPORT ACROSS THE BLOOD-BRAIN BARRIER, P91
[50]   Phosphoinositide 3-kinases: A conserved family of signal transducers [J].
Vanhaesebroeck, B ;
Leevers, SJ ;
Panayotou, G ;
Waterfield, MD .
TRENDS IN BIOCHEMICAL SCIENCES, 1997, 22 (07) :267-272