TNF-TNFR2/p75 signaling inhibits early and increases delayed nontargeted effects in bone marrow-derived endothelial progenitor cells

Sharath P. Sasi, Jin Song, Daniel Park, Heiko Enderling, J. Tyson McDonald, Hannah Gee, Brittany Garrity, Alexander Shtifman, Xinhua Yan, Kenneth Walsh, Mohan Natarajan, Raj Kishore, David A. Goukassian

Research output: Contribution to journalArticlepeer-review

14 Scopus citations


TNF-α, a pro-inflammatory cytokine, is highly expressed after being irradiated (IR) and is implicated in mediating radiobiological bystander responses (RBRs). Little is known about specific TNF receptors in regulating TNF-induced RBR in bone marrow-derived endothelial progenitor cells (BM-EPCs). Full body γ-IR WT BM-EPCs showed a biphasic response: slow decay of p-H2AX foci during the initial 24 h and increase between 24 h and 7 days post-IR, indicating a significant RBR in BM-EPCs in vivo. Individual TNF receptor (TNFR) signaling in RBR was evaluated in BM-EPCs from WT, TNFR1/p55KO, and TNFR2/p75KO mice, in vitro. Compared with WT, early RBR (1-5 h) were inhibited in p55KO and p75KO EPCs, whereas delayedRBR(3-5 days) were amplified inp55KOEPCs, suggesting a possible role for TNFR2/p75 signaling in delayed RBR. Neutralizing TNF in γIR conditioned media (CM) of WT and p55KO BM-EPCs largely abolished RBR in both cell types. ELISA protein profiling ofWTand p55KO EPCγ-IR-CM over 5 days showed significant increases in several pro-inflammatory cytokines, including TNF-α, IL-1α (Interleukin-1 alpha), RANTES (regulated on activation, normal T cell expressed and secreted), and MCP-1. In vitro treatments with murine recombinant (rm) TNF-α and rmIL-1α, but not rmMCP-1 or rmRANTES, increased the formation of p-H2AX foci in nonirradiated p55KO EPCs. We conclude that TNF-TNFR2 signaling may induce RBR in naïve BM-EPCs and that blocking TNF-TNFR2 signaling may prevent delayed RBR in BM-EPCs, conceivably, in bone marrow milieu in general.

Original languageEnglish (US)
Pages (from-to)14178-14193
Number of pages16
JournalJournal of Biological Chemistry
Issue number20
StatePublished - May 16 2014

ASJC Scopus subject areas

  • Molecular Biology
  • Biochemistry
  • Cell Biology


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