Erythropoietin and Engineered Innate Repair Activators

  • Michael Brines
  • Anthony Cerami
Part of the Methods in Molecular Biology book series (MIMB, volume 982)


Erythropoietin (EPO) is a pleiotropic type I cytokine that has been identified as a major endogenous tissue protective molecule. In response to injury, EPO and a distinct receptor are expressed with a characteristic temporal and spatial expression pattern. Together, these serve to limit injury and to initiate repair. Administration of EPO in the setting of injury has been shown to be beneficial in a multitude of preclinical models. However, translation into the clinic has been hampered by EPO’s adverse effects, including promotion of thrombosis. Recently, engineered molecules based on EPO’s structure–activity relationships have been developed that are devoid of hematopoietic effects. These compounds are promising candidates for treatment of a wide variety of acute and chronic diseases.

Key words

Innate immune response Inflammation Tissue damage Tissue protection Healing Drug design Type 1 cytokine 


Disclosure of Interest

The authors are officers of Araim Pharmaceuticals and currently hold stocks/shares in the company.


  1. 1.
    Jelkmann W (2007) Erythropoietin after a century of research: younger than ever. Eur J Haematol 78:183–205PubMedCrossRefGoogle Scholar
  2. 2.
    Marti HH, Wenger RH, Rivas LA et al (1996) Erythropoietin gene expression in human, monkey and murine brain. Eur J Neurosci 8:666–676PubMedCrossRefGoogle Scholar
  3. 3.
    Westenfelder C, Biddle DL, Baranowski RL (1999) Human, rat, and mouse kidney cells express functional erythropoietin receptors. Kidney Int 55:808–820PubMedCrossRefGoogle Scholar
  4. 4.
    Masuda S, Okano M, Yamagishi K, Nagao M, Ueda M, Sasaki R (1994) A novel site of erythropoietin production. Oxygen-dependent production in cultured rat astrocytes. J Biol Chem 269:19488–19493PubMedGoogle Scholar
  5. 5.
    Morishita E, Masuda S, Nagao M, Yasuda Y, Sasaki R (1997) Erythropoietin receptor is expressed in rat hippocampal and cerebral cortical neurons, and erythropoietin prevents in vitro glutamate-induced neuronal death. Neuroscience 76:105–116PubMedCrossRefGoogle Scholar
  6. 6.
    Brines ML, Ghezzi P, Keenan S et al (2000) Erythropoietin crosses the blood–brain barrier to protect against experimental brain injury. Proc Natl Acad Sci U S A 97:10526–10531PubMedCrossRefGoogle Scholar
  7. 7.
    Erbayraktar S, Grasso G, Sfacteria A et al (2003) Asialoerythropoietin is a nonerythropoietic cytokine with broad neuroprotective activity in vivo. Proc Natl Acad Sci U S A 100:6741–6746PubMedCrossRefGoogle Scholar
  8. 8.
    Fisher JW (2003) Erythropoietin: physiology and pharmacology update. Exp Biol Med (Maywood) 228:1–14Google Scholar
  9. 9.
    Pinto JP, Ribeiro S, Pontes H et al (2008) Erythropoietin mediates hepcidin expression in hepatocytes through EPOR signaling and regulation of C/EBPalpha. Blood 111:5727–5733PubMedCrossRefGoogle Scholar
  10. 10.
    Brines M, Cerami A (2008) Erythropoietin-mediated tissue protection: reducing collateral damage from the primary injury response. J Intern Med 264:405–432PubMedCrossRefGoogle Scholar
  11. 11.
    Anagnostou A, Lee ES, Kessimian N, Levinson R, Steiner M (1990) Erythropoietin has a mitogenic and positive chemotactic effect on endothelial cells. Proc Natl Acad Sci U S A 87:5978–5982PubMedCrossRefGoogle Scholar
  12. 12.
    Masuda S, Nagao M, Takahata K et al (1993) Functional erythropoietin receptor of the cells with neural characteristics. Comparison with receptor properties of erythroid cells. J Biol Chem 268:11208–11216PubMedGoogle Scholar
  13. 13.
    Imai N, Higuchi M, Kawamura A et al (1990) Physicochemical and biological characterization of asialoerythropoietin. Suppressive effects of sialic acid in the expression of biological activity of human erythropoietin in vitro. Eur J Biochem 194:457–462PubMedCrossRefGoogle Scholar
  14. 14.
    Cheetham JC, Smith DM, Aoki KH et al (1998) NMR structure of human erythropoietin and a comparison with its receptor bound conformation. Nat Struct Biol 5:861–866PubMedCrossRefGoogle Scholar
  15. 15.
    Leist M, Ghezzi P, Grasso G et al (2004) Derivatives of erythropoietin that are tissue protective but not erythropoietic. Science 305:239–242PubMedCrossRefGoogle Scholar
  16. 16.
    Brines M, Grasso G, Fiordaliso F et al (2004) Erythropoietin mediates tissue protection through an erythropoietin and common beta-subunit heteroreceptor. Proc Natl Acad Sci U S A 101:14907–14912PubMedCrossRefGoogle Scholar
  17. 17.
    Lopez AF, Hercus TR, Ekert P et al (2010) Molecular basis of cytokine receptor activation. IUBMB Life 62:509–518PubMedCrossRefGoogle Scholar
  18. 18.
    Jubinsky PT, Krijanovski OI, Nathan DG, Tavernier J, Sieff CA (1997) The beta chain of the interleukin-3 receptor functionally associates with the erythropoietin receptor. Blood 90:1867–1873PubMedGoogle Scholar
  19. 19.
    Brines M, Cerami A (2012) The receptor that tames the innate immune response. Mol Med 18(1):486–496PubMedGoogle Scholar
  20. 20.
    Corwin HL, Gettinger A, Fabian TC et al (2007) Efficacy and safety of epoetin alfa in critically ill patients. N Engl J Med 357:965–976PubMedCrossRefGoogle Scholar
  21. 21.
    Brines M, Patel NS, Villa P et al (2008) Nonerythropoietic, tissue-protective peptides derived from the tertiary structure of erythropoietin. Proc Natl Acad Sci U S A 105:10925–10930PubMedCrossRefGoogle Scholar
  22. 22.
    Nogawa-Kosaka N, Hirose T, Kosaka N et al (2010) Structural and biological properties of erythropoietin in Xenopus laevis. Exp Hematol 38:363–372PubMedCrossRefGoogle Scholar
  23. 23.
    Konishi Y, Chui DH, Hirose H, Kunishita T, Tabira T (1993) Trophic effect of erythropoietin and other hematopoietic factors on central cholinergic neurons in vitro and in vivo. Brain Res 609:29–35PubMedCrossRefGoogle Scholar
  24. 24.
    Mahmood A, Lu D, Qu C et al (2007) Treatment of traumatic brain injury in rats with erythropoietin and carbamylated erythropoietin. J Neurosurg 107:392–397PubMedCrossRefGoogle Scholar
  25. 25.
    van der Meer P, Lipsic E, Henning RH et al (2005) Erythropoietin induces neovascularization and improves cardiac function in rats with heart failure after myocardial infarction. J Am Coll Cardiol 46:125–133PubMedCrossRefGoogle Scholar
  26. 26.
    Erbayraktar Z, Erbayraktar S, Yilmaz O, Cerami A, Coleman T, Brines M (2009) Nonerythropoietic tissue protective compounds are highly effective facilitators of wound healing. Mol Med 15:235–241PubMedCrossRefGoogle Scholar
  27. 27.
    Su KH, Shyue SK, Kou YR et al (2011) Beta common receptor integrates the erythropoietin signaling in activation of endothelial nitric oxide synthase. J Cell Physiol 226(12):3330–3339PubMedCrossRefGoogle Scholar
  28. 28.
    Sautina L, Sautin Y, Beem E et al (2010) Induction of nitric oxide by erythropoietin is mediated by the beta common receptor and requires interaction with VEGF receptor 2. Blood 115:896–905PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2013

Authors and Affiliations

  • Michael Brines
    • 1
  • Anthony Cerami
    • 2
  1. 1.Araim Pharmaceuticals, Inc.OssiningUSA
  2. 2.Araim PharmaceuticalsOssiningUSA

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