Immunology Limiting Inflammatory Signaling with EPO

Nancy R. Gough

Science Signaling, AAAS, Washington, DC 20005, USA

Erythropoietin (EPO) is best known as the cytokine that promotes red blood cell production. However, EPO receptors (EPORs) are also present in nonerythroid cells, where they heterodimerize with β common receptors (βcRs), and have been reported to regulate apoptotic signaling pathways. Nairz et al. found that EPORs and βcRs were abundant macrophages and that addition of EPO to cultured macrophages caused a decrease in the accumulation of the end product of the nitric oxide pathway and reduced release of tumor necrosis factor– (TNF-) and interleukin-6 (IL-6) from lipopolysaccharide (LPS)–treated macrophages, and this was accompanied by a decrease in the abundance of transcripts for inducible nitric oxide synthase (iNOS), TNF-, and IL-6. Electromobility shift assays revealed that EPO inhibited the DNA-binding activity of the p65 subunit of nuclear factor B (NF-B). Pretreatment with a Janus kinase 2 (JAK2) inhibitor abolished the inhibitory effects of EPO on macrophage activation in response to LPS. In vitro and in vivo, EPO treatment increased bacterial load due to Salmonella typhimurium infection (and reduced survival of the infected mice). Injection of an EPO-neutralizing antibody improved survival of the infected mice and reduced bacterial load. The effect of EPO on S. typhimurium infection was absent in Epor^–/– mice. In two models of mouse colitis, EPO reduced the severity of the tissue inflammation, and this was accompanied by reduced DNA binding of p65 and reduced abundance of mRNAs for iNOS, TNF-, IL-5, IL-12, and IL-23. Thus, EPO appears to limit proinflammatory signaling, which has important potential therapeutic applications both in infectious disease and noninfectious inflammatory conditions.

M. Nairz, A. Schroll, A. R. Moschen, T. Sonnweber, M. Theurl, I. Theurl, N. Taub, C. Jamnig, D. Neurauter, L. A. Huber, H. Tilg, P. L. Moser, G. Weiss, Erythropoietin contrastingly affects bacterial infection and experimental colitis by inhibiting nuclear factor-B-inducible immune pathways. Immunity 34, 61–74 (2011). [PubMed]

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