Erythropoietin mediates tissue protection through an erythropoietin and common beta-subunit heteroreceptor

Giovanni Grasso, Pietro Ghezzi, Eileen Pobre, Anthony Cerami, Qiao-Wen Xie, Fabio Fiordaliso, Michael Brines, Giovanni Grasso, John Smart, Carla Hand, Chiao-Ju Su-Rick, Carla Hand, Alessandra Sfacteria, Maddalena Fratelli, Roberto Latini, Daniel Gomez, Deborah Diaz, Qiao-Wen Xie, Thomas Coleman, Antonio Cerami

Risultato della ricerca: Articlepeer review

530 Citazioni (Scopus)

Abstract

The cytokine erythropoietin (Epo) is tissue-protective in preclinical models of ischemic, traumatic, toxic, and inflammatory injuries. We have recently characterized Epo derivatives that do not bind to the Epo receptor (EpoR) yet are tissue-protective. For example, carbamylated Epo (CEpo) does not stimulate erythropoiesis, yet it prevents tissue injury in a wide variety of in vivo and in vitro models. These observations suggest that another receptor is responsible for the tissue-protective actions of Epo. Notably, prior investigation suggests that EpoR physically interacts with the common beta receptor (betacR), the signal-transducing subunit shared by the granulocyte-macrophage colony stimulating factor, and the IL-3 and IL-5 receptors. However, because betacR knockout mice exhibit normal erythrocyte maturation, betacR is not required for erythropoiesis. We hypothesized that betacR in combination with the EpoR expressed by nonhematopoietic cells constitutes a tissue-protective receptor. In support of this hypothesis, membrane proteins prepared from rat brain, heart, liver, or kidney were greatly enriched in EpoR after passage over either Epo or CEpo columns but covalently bound in a complex with betacR. Further, antibodies against EpoR coimmunoprecipitated betacR from membranes prepared from neuronal-like P-19 cells that respond to Epo-induced tissue protection. Immunocytochemical studies of spinal cord neurons and cardiomyocytes protected by Epo demonstrated cellular colocalization of Epo betacR and EpoR. Finally, as predicted by the hypothesis, neither Epo nor CEpo was active in cardiomyocyte or spinal cord injury models performed in the betacR knockout mouse. These data support the concept that EpoR and betacR comprise a tissue-protective heteroreceptor.
Lingua originaleEnglish
pagine (da-a)14907-14912
Numero di pagine6
RivistaProceedings of the National Academy of Sciences of the United States of America
Volume101
Stato di pubblicazionePublished - 2004

All Science Journal Classification (ASJC) codes

  • General

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