Peroxiredoxin 1 stimulates secretion of proinflammatory cytokines by binding to TLR4.
Peroxiredoxin 1 (Prx1) is an antioxidant and molecular chaperone that can be secreted from tumor cells. Prx1 is overexpressed in many cancers, and elevation of Prx1 is associated with poor clinical outcome. In the current study, we demonstrate that incubation of Prx1 with thioglycollate-elicited murine macrophages or immature bone marrow-derived dendritic cells resulted in TLR4-dependent secretion of TNF-alpha and IL-6 and dendritic cell maturation. Optimal secretion of cytokines in response to Prx1 was dependent upon serum and required CD14 and MD2. Binding of Prx1 to thioglycollate macrophages occurred within minutes and resulted in TLR4 endocytosis. Prx1 interaction with TLR4 was independent of its peroxidase activity and appeared to be dependent on its chaperone activity and ability to form decamers. Cytokine expression occurred via the TLR-MyD88 signaling pathway, which resulted in nuclear translocation and activation of NF-kappaB. These findings suggest that Prx1 may act as danger signal similar to other TLR4-binding chaperone molecules such as HSP72.
Riddell
Jonah R
JR
Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
Wang
Xiang-Yang
XY
Minderman
Hans
H
Gollnick
Sandra O
SO
D000818:Animals; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism*; D003713:Dendritic Cells / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D018832:Molecular Chaperones; D016328:NF-kappa B / Q000378:metabolism; D054464:Peroxiredoxins / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D011485:Protein Binding; D055503:Protein Multimerization; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000378:metabolism*
D016207:Cytokines; D018836:Inflammation Mediators; D018832:Molecular Chaperones; D016328:NF-kappa B; D051197:Toll-Like Receptor 4; D054464:Peroxiredoxins