Pro-atherogenic effect of interleukin-4 in endothelial cells: modulation of oxidative stress, nitric oxide and monocyte chemoattractant protein-1 expression.
BACKGROUND
Although considered as an anti-inflammatory cytokine, interleukin-4 (IL-4) has been shown to be pro-atherogenic in mice models of atherosclerosis.


OBJECTIVE
In order to elucidate this paradox, we have investigated the effects of IL-4 on characteristic atherogenic parameters in human umbilical vein endothelial cells (HUVECs): production of reactive oxygen species, expression of monocyte chemoattractant protein-1 (MCP-1) and nitric oxide (NO) bioavailability.


RESULTS
Incubation of HUVECs with IL-4 resulted in an increased production of reactive oxygen species and extracellular O(2)(-)(*) measured using fluorogenic probes and Cytochrome c that was inhibited by superoxide dismutase or gp91ds-tat, a selective NADPH oxidase inhibitor. The latter also inhibited IL-4 induced over-expression of MCP-1 mRNA measured by classical and real time RT-PCR. Incubation of HUVECs with IL-4 reduced thrombin-induced NO release, detected by electrochemistry, an effect which was reversed by incubation with superoxide dismutase. Both production of reactive oxygen species and MCP-1 mRNA over-expression induced by IL-4 were fully inhibited by selective inhibitors of phosphatidyl inositol 3-kinase.


CONCLUSIONS
The data demonstrate that IL-4 up-regulates the expression of MCP-1 and decreases NO bioavailability through activation of NADPH oxidase in endothelial cells. These results are in favor of a pro-inflammatory and pro-atherogenic effect of IL-4 in vascular tissues.
Walch
L
L
UMR7131 CNRS/Université Pierre et Marie Curie (Paris 6), Hôpital Broussais, 102 rue Didot, 75014 Paris, France. laurence.walch@brs.ap-hop-paris.fr
Massade
L
L
Dufilho
M
M
Brunet
A
A
Rendu
F
F
D001095:Arachidonic Acids / Q000494:pharmacology; D050197:Atherosclerosis / Q000276:immunology / Q000378:metabolism*; D018932:Chemokine CCL2 / Q000235:genetics* / Q000378:metabolism; D002867:Chromones / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D015847:Interleukin-4 / Q000378:metabolism* / Q000494:pharmacology; D009025:Morpholines / Q000494:pharmacology; D019255:NADPH Oxidases / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects / Q000276:immunology*; D012333:RNA, Messenger / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000494:pharmacology; D014471:Umbilical Veins / Q000166:cytology
D001095:Arachidonic Acids; C111835:CCL2 protein, human; D018932:Chemokine CCL2; D002867:Chromones; D004791:Enzyme Inhibitors; C508598:IL4 protein, human; D009025:Morpholines; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; C081565:arachidonyltrifluoromethane; D015847:Interleukin-4; D009569:Nitric Oxide; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D052247:Nitric Oxide Synthase Type II; D019255:NADPH Oxidases