The lectin-like domain of TNF protects from listeriolysin-induced hyperpermeability in human pulmonary microvascular endothelial cells - a crucial role for protein kinase C-alpha inhibition.
Listeriosis can lead to potentially lethal pulmonary complications in newborns and immune compromised patients, characterized by extensive permeability edema. Listeriolysin (LLO), the main virulence factor of Listeria monocytogenes, induces a dose-dependent hyperpermeability in monolayers of human lung microvascular endothelial cells in vitro. The permeability increasing activity of LLO, which is accompanied by an increased reactive oxygen species (ROS) generation, RhoA activation and myosin light chain (MLC) phosphorylation, can be completely inhibited by the protein kinase C (PKC) alpha/beta inhibitor GO6976, indicating a crucial role for PKC in the induction of barrier dysfunction. The TNF-derived TIP peptide, which mimics the lectin-like domain of the cytokine, blunts LLO-induced hyperpermeability in vitro, upon inhibiting LLO-induced protein kinase C-alpha activation, ROS generation and MLC phosphorylation and upon restoring the RhoA/Rac 1 balance. These results indicate that the lectin-like domain of TNF has a potential therapeutic value in protecting from LLO-induced pulmonary endothelial hyperpermeability.
Xiong
Chenling
C
Medical College of Georgia, Augusta, GA, USA.
Yang
Guang
G
Kumar
Sanjiv
S
Aggarwal
Saurabh
S
Leustik
Martin
M
Snead
Connie
C
Hamacher
Juerg
J
Fischer
Bernhard
B
Umapathy
Nagavedi S
NS
Hossain
Hamid
H
Wendel
Albrecht
A
Catravas
John D
JD
Verin
Alexander D
AD
Fulton
David
D
Black
Stephen M
SM
Chakraborty
Trinad
T
Lucas
Rudolf
R
D000818:Animals; D001427:Bacterial Toxins / Q000633:toxicity*; D002417:Cattle; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000378:metabolism* / Q000382:microbiology; D006360:Heat-Shock Proteins / Q000633:toxicity*; D006460:Hemolysin Proteins / Q000633:toxicity*; D006801:Humans; D008089:Listeria monocytogenes / Q000472:pathogenicity*; D008168:Lung / Q000166:cytology / Q000378:metabolism / Q000382:microbiology; D018994:Myosin Light Chains / Q000378:metabolism; D010455:Peptides / Q000494:pharmacology; D010539:Permeability; D010766:Phosphorylation; D051571:Protein Kinase C-alpha / Q000037:antagonists & inhibitors; D011651:Pulmonary Artery / Q000378:metabolism / Q000382:microbiology; D017382:Reactive Oxygen Species / Q000378:metabolism; D012756:Sheep; D014409:Tumor Necrosis Factor-alpha / Q000737:chemistry / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
D001427:Bacterial Toxins; D006360:Heat-Shock Proteins; D006460:Hemolysin Proteins; D018994:Myosin Light Chains; D010455:Peptides; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; C521715:pepBs1-Ac peptide; D051571:Protein Kinase C-alpha; D020742:rhoA GTP-Binding Protein; C038705:hlyA protein, Listeria monocytogenes