Extrahematopoietic Actions of Erythropoietin

Abstract Erythropoietin (EPO), a member of the type I cytokine family, is an evolutionarily ancient molecule. Similar to other cytokines, EPO performs diverse biological roles. In addition to its key function as the hormone driving hematopoiesis, results of a recent study have shown that EPO is also a component of the innate immune response. Specifically, tissue injury and stress stimulate the local synthesis of EPO by a variety of cell types. This EPO subsequently acts in a protective mode by signaling through an EPO receptor isoform which is also expressed as a response to inflammation or cellular damage and is distinct from the homodimeric hematopoietic receptor. Activation of this receptor antagonizes proinflammatory responses, is cytoprotective, and promotes tissue repair. Additionally, EPO has been shown to play an important role in metabolism and body mass regulation. Unfortunately, use of recombinant EPO for tissue protection is problematic as it activates both receptor types, resulting in unacceptable hematopoietic adverse effects. Efforts are currently underway to develop clinically useful nonerythropoietic analogs that selectively target the tissue protective receptor without activating the hematopoietic system.