Erythropoietin contrastingly affects bacterial infection and experimental colitis by inhibiting nuclear factor-κB-inducible immune pathways.
Erythropoietin (EPO) is the principal cytokine regulating erythropoiesis through its receptor, EPOR. Interestingly, EPORs are also found on immune cells with incompletely understood functions. Here, we show that EPO inhibits the induction of proinflammatory genes including tumor necrosis factor (TNF)-α and inducible nitric oxide (NO) synthase in activated macrophages, which is mechanistically attributable to blockage of nuclear factor (NF)-κB p65 activation by EPO. Accordingly, in systemic Salmonella infection, treatment of mice with EPO results in reduced survival and impaired pathogen clearance because of diminished formation of anti-microbial effector molecules such as TNF-α and NO. However, neutralization of endogenous EPO or genetic ablation of Epor promotes Salmonella elimination. In contrast, in chemically induced colitis, EPO-EPOR interaction decreases the production of NF-κB-inducible immune mediators, thus limiting tissue damage and ameliorating disease severity. These immune-modulatory effects of EPO may be of therapeutic relevance in infectious and inflammatory diseases.
Department of Internal Medicine I, Clinical Immunology and Infectious Diseases, Innsbruck Medical University, 6020 Innsbruck, Austria.
Manfred
M
Nairz
Andrea
A
Schroll
Alexander R
AR
Moschen
Thomas
T
Sonnweber
Milan
M
Theurl
Igor
I
Theurl
Nicole
N
Taub
Christina
C
Jamnig
Daniela
D
Neurauter
Lukas A
LA
Huber
Herbert
H
Tilg
Patrizia L
PL
Moser
Günter
G
Weiss
D000818:Animals; D002460:Cell Line; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy / Q000276:immunology*; D016264:Dextran Sulfate / Q000008:administration & dosage; D004921:Erythropoietin / Q000008:administration & dosage*; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism*; D009569:Nitric Oxide / Q000276:immunology / Q000378:metabolism; D017467:Receptors, Erythropoietin / Q000235:genetics / Q000378:metabolism*; D012475:Salmonella / Q000276:immunology* / Q000472:pathogenicity; D012480:Salmonella Infections / Q000188:drug therapy / Q000276:immunology*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D014302:Trinitrobenzenesulfonic Acid / Q000008:administration & dosage; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology / Q000378:metabolism
D018836:Inflammation Mediators; D016328:NF-kappa B; D017467:Receptors, Erythropoietin; D014409:Tumor Necrosis Factor-alpha; D004921:Erythropoietin; D009569:Nitric Oxide; D014302:Trinitrobenzenesulfonic Acid; D016264:Dextran Sulfate
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