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

被引:529
作者
Brines, M
Grasso, G
Fiordaliso, F
Sfacteria, A
Ghezzi, P
Fratelli, M
Latini, R
Xie, QW
Smart, J
Su-Rick, CJ
Pobre, E
Diaz, D
Gomez, D
Hand, C
Coleman, T
Cerami, A
机构
[1] Kenneth S Warren Inst, Kitchawan, NY 10562 USA
[2] Warren Pharmaceut Inc, Ossining, NY 10563 USA
[3] Mario Negri Inst Pharmacol Res, I-20157 Milan, Italy
[4] Univ Messina, I-98122 Messina, Italy
关键词
D O I
10.1073/pnas.0406491101
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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, carbarrylated 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.
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页码:14907 / 14912
页数:6
相关论文
共 33 条
[21]  
MASUDA S, 1993, J BIOL CHEM, V268, P11208
[22]   Molecular assembly of the ternary granulocyte-macrophage colony-stimulating factor receptor complex [J].
McClure, BJ ;
Hercus, TR ;
Cambareri, BA ;
Woodcock, JM ;
Bagley, CJ ;
Howlett, GJ ;
Lopez, AF .
BLOOD, 2003, 101 (04) :1308-1315
[23]  
Muller-Newen Gerhard, 2003, Sci STKE, V2003, pPE40, DOI 10.1126/stke.2003.201.pe40
[24]   MICE DEFICIENT FOR THE IL-3/GM-CSF/IL-5 BETA-C RECEPTOR EXHIBIT LUNG PATHOLOGY AND IMPAIRED IMMUNE-RESPONSE, WHILE BETA-IL3 RECEPTOR-DEFICIENT MICE ARE NORMAL [J].
NISHINAKAMURA, R ;
NAKAYAMA, N ;
HIRABAYASHI, Y ;
INOUE, T ;
AUD, D ;
MCNEIL, T ;
AZUMA, S ;
YOSHIDA, S ;
TOYODA, Y ;
ARAI, K ;
MIYAJIMA, A ;
MURRAY, R .
IMMUNITY, 1995, 2 (03) :211-222
[25]   Distinct changes in pulmonary surfactant homeostasis in common β-chain-and GM-CSF-deficient mice [J].
Reed, JA ;
Ikegami, M ;
Robb, L ;
Begley, CG ;
Ross, G ;
Whitsett, JA .
AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY, 2000, 278 (06) :L1164-L1171
[26]  
Rossjohn J, 2000, BLOOD, V95, P2491
[27]   Reassessment of interactions between hematopoietic receptors using common beta-chain and interleukin-3-specific receptor beta-chain-null cells: no evidence of functional interactions with receptors for erythropoietin, granulocyte colony-stimulating factor, or stem cell factor [J].
Scott, CL ;
Robb, L ;
Papaevangeliou, B ;
Mansfield, R ;
Nicola, NA ;
Begley, CG .
BLOOD, 2000, 96 (04) :1588-1590
[28]   Erythropoietin and erythropoietin receptor in human ischemic/hypoxic brain [J].
Sirén, AL ;
Knerlich, F ;
Poser, W ;
Gleiter, CH ;
Brück, W ;
Ehrenreich, H .
ACTA NEUROPATHOLOGICA, 2001, 101 (03) :271-276
[29]   Effects of erythropoietin on platelet reactivity and thrombopoiesis in humans [J].
Stohlawetz, PJ ;
Dzirlo, L ;
Hergovich, N ;
Lackner, E ;
Mensik, C ;
Eichler, HG ;
Kabrna, E ;
Geissler, K ;
Jilma, B .
BLOOD, 2000, 95 (09) :2983-2989
[30]   Interleukin-3 and interleukin-3 receptors in the brain [J].
Tabira, T ;
Chui, DH ;
Fan, JP ;
Shirabe, T ;
Konishi, Y .
NEUROIMMUNOMODULATION: MOLECULAR ASPECTS, INTEGRATIVE SYSTEMS, AND CLINICAL ADVANCES, 1998, 840 :107-116