Modulation of cellular stress response via the erythropoietin/CD131 heteroreceptor complex in mouse mesenchymal-derived cells

Stefan Bohr, Suraj J. Patel, Radovan Vasko, Keyue Shen, Arvin Iracheta-Vellve, Jungwoo Lee, Shyam Sundhar Bale, Nilay Chakraborty, Michael Brines, Anthony Cerami, Francois Berthiaume, Martin L. Yarmush

Research output: Contribution to journalArticlepeer-review

21 Scopus citations

Abstract

Abstract: Tissue-protective properties of erythropoietin (EPO) have let to the discovery of an alternative EPO signaling via an EPO-R/CD131 receptor complex which can now be specifically targeted through pharmaceutically designed short sequence peptides such as ARA290. However, little is still known about specific functions of alternative EPO signaling in defined cell populations. In this study, we investigated effects of signaling through EPO-R/CD131 complex on cellular stress responses and pro-inflammatory activation in different mesenchymal-derived phenotypes. We show that anti-apoptotic, anti-inflammatory effects of ARA290 and EPO coincide with the externalization of CD131 receptor component as an immediate response to cellular stress. In addition, alternative EPO signaling strongly modulated transcriptional, translational, or metabolic responses after stressor removal. Specifically, we saw that ARA290 was able to overcome a TNFα-mediated inhibition of transcription factor activation related to cell stress responses, most notably of serum response factor (SRF), heat shock transcription factor protein 1 (HSF1), and activator protein 1 (AP1). We conclude that alternative EPO signaling acts as a modulator of pro-inflammatory signaling pathways and likely plays a role in restoring tissue homeostasis.

Original languageEnglish (US)
Pages (from-to)199-210
Number of pages12
JournalJournal of Molecular Medicine
Volume93
Issue number2
DOIs
StatePublished - Feb 2015
Externally publishedYes

Keywords

  • Apoptosis
  • ARA290
  • Heat shock
  • Homeostasis
  • Mesenchymal stem cells
  • Oxidative stress
  • TNFα

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery
  • Genetics(clinical)

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