TY - JOUR
T1 - The lectin-like domain of TNF protects from listeriolysin-induced hyperpermeability in human pulmonary microvascular endothelial cells - A crucial role for protein kinase C-α inhibition
AU - Xiong, Chenling
AU - Yang, Guang
AU - Kumar, Sanjiv
AU - Aggarwal, Saurabh
AU - Leustik, Martin
AU - Snead, Connie
AU - Hamacher, Juerg
AU - Fischer, Bernhard
AU - Siddaramappa, Umapathy N
AU - Hossain, Hamid
AU - Wendel, Albrecht
AU - Catravas, John D.
AU - Verin, Alexander Dmitriyevich
AU - Fulton, David J
AU - Black, Stephen Matthew
AU - Chakraborty, Trinad
AU - Lucas, Rudolf
N1 - Funding Information:
The authors would like to thank Dr. Supriya Sridmar for help with the figures. This work was supported in part by a BMBF-Clinical Research Group in Infectious Diseases grant to HH. ML. and TC. TC. is moreover supported by funds made available by the BMBF through NGFN-2 . This work was partially supported by an industry grant from Apeptico, Vienna, Austria (RL., GY, and CX) and HL67841 (SMB). This work was also supported by a Programmatic Development award (to RL, SMB, JC, DF, and AV) and Seed Awards (to SK) from the Cardiovascular Discovery Institute of the Medical College of Georgia .
PY - 2010/5
Y1 - 2010/5
N2 - 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) α/β inhibitor GÖ6976, 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-α 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.
AB - 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) α/β inhibitor GÖ6976, 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-α 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.
KW - Endothelial hyperpermeability
KW - Listeriolysin
KW - Protein kinase C
KW - Reactive oxygen species
KW - TNF
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U2 - 10.1016/j.vph.2009.12.010
DO - 10.1016/j.vph.2009.12.010
M3 - Article
C2 - 20074664
AN - SCOPUS:77950918344
SN - 1537-1891
VL - 52
SP - 207
EP - 213
JO - Vascular Pharmacology
JF - Vascular Pharmacology
IS - 5-6
ER -