TY - JOUR
T1 - TNF-TNFR2/p75 signaling inhibits early and increases delayed nontargeted effects in bone marrow-derived endothelial progenitor cells
AU - Sasi, Sharath P.
AU - Song, Jin
AU - Park, Daniel
AU - Enderling, Heiko
AU - McDonald, J. Tyson
AU - Gee, Hannah
AU - Garrity, Brittany
AU - Shtifman, Alexander
AU - Yan, Xinhua
AU - Walsh, Kenneth
AU - Natarajan, Mohan
AU - Kishore, Raj
AU - Goukassian, David A.
PY - 2014/5/16
Y1 - 2014/5/16
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84900992801&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84900992801&partnerID=8YFLogxK
U2 - 10.1074/jbc.M114.567743
DO - 10.1074/jbc.M114.567743
M3 - Article
C2 - 24711449
AN - SCOPUS:84900992801
SN - 0021-9258
VL - 289
SP - 14178
EP - 14193
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 20
ER -