Role of C/EBP Delta in IR-Induced Sepsis
Technical Report,01 Sep 2015,31 Aug 2019
University of Arkansas for Medical Sciences Little Rock United States
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It is known that exposure to ionizing radiation IR induces a plethora of responses in the cells to counteract oxidative stress, DNA damage response and inflammation by inducing the expression of inflammatory and anti-inflammatory cytokines. We have previously shown that Cebpd-knockout KO mice are highly sensitive to IR and the underlying cause of lethality is due to injury to the intestine and bone marrow. In this study, we investigated whether impaired inflammation signaling and oxidativenitrosative stress promoted radiation-induced intestinal injury and sepsis-associated lethality of Cebpd-- mice after exposure to total body irradiation. We showed that Cebpd-KO mice display increased expression of the pro-inflammatory cytokines. We also uncovered that the IR-induced upregulation of TLR4 signaling in Cebpd-KO mice is due to upregulation of TRAF6 a positive regulator and decrease in expression of TOLLIP a negative regulator. We also found that Cebpd is essential for gamma tocotrienol-mediated protection against radiation-induced intestinal and bone marrow injury. Lastly, our results reveal that Cebpd-deficiency does not perturb the response of KO macrophages to promote increased intestinal injury in response to TBI exposure. Lastly, we also found that treatment with TLR4 inhibitor-C34immediately post-irradiation showed a significant protection of intestinal crypts at day 3.5 post-10 Gy, however the effect on overall survival remains unexplored. Given that TLR4 does play an important role in intestinal homeostasis as well as in hematopoietic system, the time and dosing regimen will play a critical role. In this regards, the pharmacokinetics and pharmacodynamics of the TLR4 inhibitor C34will need to be determined.