Steward Research And Specialty Projects Corporation | Date: 2011-04-07
The invention provides methods for the treatments of neoplasia featuring agents that interfere with the expression or activity of a TNFa receptor.
Sasi S.P.,Steward Research and Specialty Projects Corporation |
Song J.,Steward Research and Specialty Projects Corporation |
Park D.,Steward Research and Specialty Projects Corporation |
Enderling H.,Genesys Systems |
And 17 more authors.
Journal of Biological Chemistry | Year: 2014
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. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.