title: Regulation of interleukin-4 signaling by extracellular reduction of intramolecular disulfides.
abstract: Interleukin-4 (IL-4) contains three structurally important intramolecular disulfides that are required for the bioactivity of the cytokine. We show that the cell surface of HeLa cells and endotoxin-activated monocytes can reduce IL-4 intramolecular disulfides in the extracellular space and inhibit binding of IL-4 to the IL-4Ralpha receptor. IL-4 disulfides were in vitro reduced by thioredoxin 1 (Trx1) and protein disulfide isomerase (PDI). Reduction of IL-4 disulfides by the cell surface of HeLa cells was inhibited by auranofin, an inhibitor of thioredoxin reductase that is an electron donor to both Trx1 and PDI. Both Trx1 and PDI have been shown to be located at the cell surface and our data suggests that these enzymes are involved in catalyzing reduction of IL-4 disulfides. The pro-drug N-acetylcysteine (NAC) that promotes T-helper type 1 responses was also shown to mediate the reduction of IL-4 disulfides. Our data provides evidence for a novel redox dependent pathway for regulation of cytokine activity by extracellular reduction of intramolecular disulfides at the cell surface by members of the thioredoxin enzyme family.
authors.affiliation: Department of Laboratory Medicine, Clinical Microbiology F68, Karolinska Institute, Karolinska University Hospital Huddinge, SE-14186 Stockholm, Sweden.
authors.forename: Sophie
authors.initials: S
authors.lastname: Curbo
authors.forename: Raphaël
authors.initials: R
authors.lastname: Gaudin
authors.forename: Mattias
authors.initials: M
authors.lastname: Carlsten
authors.forename: Karl-Johan
authors.initials: KJ
authors.lastname: Malmberg
authors.forename: Marita
authors.initials: M
authors.lastname: Troye-Blomberg
authors.forename: Niklas
authors.initials: N
authors.lastname: Ahlborg
authors.forename: Anna
authors.initials: A
authors.lastname: Karlsson
authors.forename: Magnus
authors.initials: M
authors.lastname: Johansson
authors.forename: Mathias
authors.initials: M
authors.lastname: Lundberg
mesh_terms: D001310:Auranofin / Q000494:pharmacology; D003553:Cystine / Q000737:chemistry / Q000378:metabolism*; D005033:Ethylmaleimide / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D015847:Interleukin-4 / Q000737:chemistry / Q000378:metabolism*; D053662:Interleukin-4 Receptor alpha Subunit / Q000737:chemistry / Q000378:metabolism*; D010084:Oxidation-Reduction; D019704:Protein Disulfide-Isomerases / Q000737:chemistry / Q000378:metabolism; D015398:Signal Transduction; D013879:Thioredoxins / Q000737:chemistry / Q000378:metabolism
chemical_list: C504000:IL4R protein, human; D053662:Interleukin-4 Receptor alpha Subunit; C491203:TXN protein, human; D015847:Interleukin-4; D001310:Auranofin; D003553:Cystine; D013879:Thioredoxins; D019704:Protein Disulfide-Isomerases; D005033:Ethylmaleimide