[Purpose] It has been hypothesized that persistent inflammation causes radiation-induced genomic instability through elevation of inflammatory cytokine levels. In the present study, we evaluated relationship between inflammation and genomic instability in the murine hematopoietic system in vivo, using two inflammation models.
[Method] Persistent inflammation was induced with graft-versus-host disease (GVHD) in (C57BL/6 x DBA/2) F1 (BDF1) and (BALB/c x C57BL/6) F1 (CBF1) mice that received hematopoietic cell transplantation from parent mice. Acute inflammation effects were assessed in C57BL/6 (B6) and BALB/c mice treated with different doses of Poly (I:C). Reticulocyte MN frequencies and inflammatory cytokine levels were measured by flow cytometry with CD71/CD61/PI staining and cytometric bead array, respectively.
[Result] MN frequencies significantly increased in both the BDF1 and CBF1 mice that received transplantation from parental B6 mice (p = 0.001, and p = 0.015, respectively). However, there was no significant change in MN frequencies in the F1 mice that received transplantation from the other parental mice. In addition, the increase of circulating TNF-α levels was profound in F1 mice receiving transplantation from B6 mice compared with those receiving transplantation from the other parental mice, and positively correlated with MN frequencies (r = 0.48 and r = 0.67 in B6-into-BDF1 and B6-into-CBF1 models, respectively). In mice with acute inflammation induced by Poly (I:C) treatment, dose-dependent increases in levels of inflammatory cytokines were observed, especially for TNF-α, as well as in frequencies of reticulocyte MN. Furthermore, the dose dependencies differed between these mouse strains.
[Conclusion] We conclude that inflammation becoming manifest with increased TNF-α level may be involved in genomic instability and that there may be a mouse strain difference in sensitivity to inflammatory response affecting genomic instability.