title: Truncated and full-length thioredoxin-1 have opposing activating and inhibitory properties for human complement with relevance to endothelial surfaces.
abstract: Thioredoxin (Trx)-1 is a small, ubiquitously expressed redox-active protein with known important cytosolic functions. However, Trx1 is also upregulated in response to various stress stimuli, is found both at the cell surface and secreted into plasma, and has known anti-inflammatory and antiapoptotic properties. Previous animal studies have demonstrated that exogenous Trx1 delivery can have therapeutic effects in a number of disease models and have implicated an interaction of Trx1 with the complement system. We found that Trx1 is expressed in a redox-active form at the surface of HUVEC and acts as an inhibitor of complement deposition in a manner dependent on its Cys-Gly-Pro-Cys active site. Inhibition occurred at the point of the C5 convertase of complement, regulating production of C5a and the membrane attack complex. A truncated form of Trx1 also exists in vivo, Trx80, which has separate nonoverlapping functions compared with the full-length Trx1. We found that Trx80 activates the classical and alternative pathways of complement activation, leading to C5a production, but the inflammatory potential of this was also limited by the binding of inhibitors C4b-binding protein and factor H. This study adds a further role to the known anti-inflammatory properties of Trx1 and highlights the difference in function between the full-length and truncated forms.
authors.affiliation: Section of Medical Protein Chemistry, Department of Laboratory Medicine, Lund University, S-205 02 Malmö, Sweden.
authors.forename: Ben C
authors.initials: BC
authors.lastname: King
authors.forename: Justyna
authors.initials: J
authors.lastname: Nowakowska
authors.forename: Christian M
authors.initials: CM
authors.lastname: Karsten
authors.forename: Jörg
authors.initials: J
authors.lastname: Köhl
authors.forename: Erik
authors.initials: E
authors.lastname: Renström
authors.forename: Anna M
authors.initials: AM
authors.lastname: Blom
mesh_terms: D000818:Animals; D003167:Complement Activation; D050577:Complement C3-C5 Convertases / Q000276:immunology / Q000378:metabolism; D050716:Complement C4b-Binding Protein / Q000276:immunology / Q000378:metabolism; D015936:Complement C5a / Q000276:immunology* / Q000378:metabolism; D017242:Complement Factor H / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D015870:Gene Expression; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D010084:Oxidation-Reduction; D010446:Peptide Fragments / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D010538:Peritonitis / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D011994:Recombinant Proteins / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction; D013879:Thioredoxins / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism
chemical_list: D050716:Complement C4b-Binding Protein; D010446:Peptide Fragments; D011994:Recombinant Proteins; C427943:Trx80 protein, human; D013879:Thioredoxins; D015936:Complement C5a; D017242:Complement Factor H; D050577:Complement C3-C5 Convertases