TNF-TNFR2/p75 Signaling Inhibits Early and Increases Delayed Non-Targeted Effects in Bone Marrow-Derived Endothelial Progenitor Cells [Signal Transduction]
April 22nd, 2014 by Sasi, S. P., Song, J., Park, D., Enderling, H., McDonald, J. T., Gee, H., Garrity, B., Shtifman, A., Yan, X., Walsh, K., Natarajan, M., Kishore, R., Goukassian, D. A.
TNF-α, a pro-inflammatory cytokine, is highly expressed after ionizing radiation (IR) and is implicated in mediating radiobiological bystander responses (RBR). 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 wild type (WT) BM-EPCs showed byphasic response: slow decay of p-H2AX foci during initial 24h and increase between 24h and 7 days post-IR, indicating a significant RBR in BM-EPCs in vivo. Individual TNF receptor signaling in RBR was evaluated in BM-EPCs from WT, TNFR1/p55KO and TNFR2/p75KO mice, in-vitro. Compared to WT, early RBR (1-5h) were inhibited in p55KO and p75KO EPCs, whereas delayed RBR (3-5d) were amplified in p55KO EPCs, suggesting 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 5d showed significant increases in several pro-inflammatory cytokines, including TNF-α, IL-1α, Rantes and MCP1. In-vitro treatments with murine recombinant (rm) rmTNF-α and rmIL-1α, but not rmMCP-1 or rmRantes increased the formation of p-H2AX foci in N-IR p55KO EPCs. We conclude that TNF-TNFR2 signaling may induce RBR in naive BM-EPCs and that blocking TNF-TNFR2 signaling may prevent delayed RBR in BM-derived EPCs, conceivably, in bone marrow milieu in general.