title: Interleukin-4 induces up-regulation of endothelial cell claudin-5 through activation of FoxO1: role in protection from complement-mediated injury.
abstract: Injury to endothelial cells (ECs) often results in cell retraction and gap formation. When caused by antigen aggregation or complement, this injury can be prevented by pretreatment of the ECs with IL-4, suggesting that IL-4 modifies the intercellular junction. Therefore, we investigated the effects of IL-4 on expression of intercellular junction proteins and whether such effects are required for IL-4-induced resistance of ECs against complement-mediated injury. We found that IL-4 induces upregulation of the junction protein claudin-5 in porcine ECs through activation of Jak/STAT6 and phosphorylation and translocation of FoxO1 from the nucleus to the cytoplasm. Increased claudin-5 expression resulted in increased transmembrane electrical resistance of the endothelial monolayer and participated in IL-4-induced protection of the ECs from complement injury. Down-regulation of FoxO1 using siRNA by itself caused up-regulation of claudin-5 expression and partial protection from cytotoxicity. This protection was enhanced by stimulation with IL-4. We previously reported that increased phospholipid synthesis and mitochondrial protection were required for IL-4-induced resistance of ECs against complement injury and now we demonstrate a contribution of claudin-5 expression in IL-4-induced protection.
authors.affiliation: From the Departments of Surgery.
authors.forename: Agustin P
authors.initials: AP
authors.lastname: Dalmasso
authors.forename: Daniel
authors.initials: D
authors.lastname: Goldish
authors.forename: Barbara A
authors.initials: BA
authors.lastname: Benson
authors.forename: Alexander K
authors.initials: AK
authors.lastname: Tsai
authors.forename: Karen R
authors.initials: KR
authors.lastname: Wasiluk
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Vercellotti
mesh_terms: D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D062507:Claudin-5 / Q000378:metabolism*; D003165:Complement System Proteins / Q000633:toxicity; D003593:Cytoplasm / Q000378:metabolism; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D015151:Immunoblotting; D015847:Interleukin-4 / Q000494:pharmacology*; D053616:Janus Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence; D010766:Phosphorylation / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D011743:Pyrimidines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D034622:RNA Interference; D050800:STAT6 Transcription Factor / Q000235:genetics / Q000378:metabolism; D013552:Swine; D015854:Up-Regulation / Q000187:drug effects*
chemical_list: D062507:Claudin-5; C499511:FOXO1A protein, pig; D051858:Forkhead Transcription Factors; C554945:PF 956980; D011743:Pyrimidines; D011758:Pyrroles; D050800:STAT6 Transcription Factor; D015847:Interleukin-4; D003165:Complement System Proteins; D053616:Janus Kinase 3
keywords: Cell Junctions; Claudin-5; Complement; Endothelium; Foxo; IL-4; Vascular Biology