TNF-TNFR2/p75 signaling inhibits early and increases delayed nontargeted effects in bone marrow-derived endothelial progenitor cells.
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 delayed RBR (3-5 days) were amplified in p55KO EPCs, suggesting a possible role for TNFR2/p75 signaling in delayed RBR. Neutralizing TNF in γ-IR conditioned media (CM) of WT and p55KO BM-EPCs largely abolished RBR in both cell types. ELISA protein profiling of WT and p55KO EPC γ-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.
From the Cardiovascular Research Center, Steward Research and Specialty Projects Corporation, Brighton, Massachusetts 02135.
Sharath P
SP
Sasi
From the Cardiovascular Research Center, Steward Research and Specialty Projects Corporation, Brighton, Massachusetts 02135.
Jin
J
Song
From the Cardiovascular Research Center, Steward Research and Specialty Projects Corporation, Brighton, Massachusetts 02135.
Daniel
D
Park
the Center of Cancer Systems Biology, GeneSys Research Institute, Boston, Massachusetts 02135, Department of Integrated Mathematical Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33612, Tufts University School of Medicine, Boston, Massachusetts 02111.
Heiko
H
Enderling
the Center of Cancer Systems Biology, GeneSys Research Institute, Boston, Massachusetts 02135, Tufts University School of Medicine, Boston, Massachusetts 02111.
J Tyson
JT
McDonald
From the Cardiovascular Research Center, Steward Research and Specialty Projects Corporation, Brighton, Massachusetts 02135.
Hannah
H
Gee
From the Cardiovascular Research Center, Steward Research and Specialty Projects Corporation, Brighton, Massachusetts 02135.
Brittany
B
Garrity
From the Cardiovascular Research Center, Steward Research and Specialty Projects Corporation, Brighton, Massachusetts 02135, Tufts University School of Medicine, Boston, Massachusetts 02111.
Alexander
A
Shtifman
From the Cardiovascular Research Center, Steward Research and Specialty Projects Corporation, Brighton, Massachusetts 02135, the Center of Cancer Systems Biology, GeneSys Research Institute, Boston, Massachusetts 02135, Tufts University School of Medicine, Boston, Massachusetts 02111.
Xinhua
X
Yan
the Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts 02118.
Kenneth
K
Walsh
the University of Texas Health Science Center, San Antonio, Texas 78229, and.
Mohan
M
Natarajan
the Feinberg Cardiovascular Research Institute, Northwestern University, Chicago, Illinois 60611.
Raj
R
Kishore
From the Cardiovascular Research Center, Steward Research and Specialty Projects Corporation, Brighton, Massachusetts 02135, Tufts University School of Medicine, Boston, Massachusetts 02111, the Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts 02118, david.goukassian@tufts.edu.
David A
DA
Goukassian
D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology*; D024201:Bystander Effect / Q000187:drug effects / Q000528:radiation effects; D066026:Endothelial Progenitor Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism* / Q000528:radiation effects; D055786:Gene Knockout Techniques; D006657:Histones / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D053582:Interleukin-1alpha / Q000494:pharmacology; D008024:Ligands; D051379:Mice; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000528:radiation effects; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism* / Q000494:pharmacology
D006657:Histones; D007334:Insulin-Like Growth Factor I; D053582:Interleukin-1alpha; D008024:Ligands; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D014409:Tumor Necrosis Factor-alpha; C475961:gamma-H2AX protein, mouse
Cytokine; DNA Damage Response; Nontargeted Effects; Radiation Biology; Receptors; Tumor Necrosis Factor (TNF)