Regulation of interleukin-4 signaling by extracellular reduction of intramolecular disulfides.
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.
Curbo
Sophie
S
Department of Laboratory Medicine, Clinical Microbiology F68, Karolinska Institute, Karolinska University Hospital Huddinge, SE-14186 Stockholm, Sweden.
Gaudin
Raphaël
R
Carlsten
Mattias
M
Malmberg
Karl-Johan
KJ
Troye-Blomberg
Marita
M
Ahlborg
Niklas
N
Karlsson
Anna
A
Johansson
Magnus
M
Lundberg
Mathias
M
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
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