Ciprofloxacin modulates cytokine/chemokine profile in serum, improves bone marrow repopulation, and limits apoptosis and autophagy in ileum after whole body ionizing irradiation combined with skin-wound trauma.

Radiation combined injury (CI) is a radiation injury (RI) combined with other types of injury, which generally leads to greater mortality than RI alone. A spectrum of specific, time-dependent pathophysiological changes is associated with CI. Of these changes, the massive release of pro-inflammatory cytokines, severe hematopoietic and gastrointestinal losses and bacterial sepsis are important treatment targets to improve survival. Ciprofloxacin (CIP) is known to have immunomodulatory effect besides the antimicrobial activity. The present study reports that CIP ameliorated pathophysiological changes unique to CI that later led to major mortality. B6D2F1/J mice received CI on day 0, by RI followed by wound trauma, and were treated with CIP (90 mg/kg p.o., q.d. within 2 h after CI through day 10). At day 10, CIP treatment not only significantly reduced pro-inflammatory cytokine and chemokine concentrations, including interleukin-6 (IL-6) and KC (i.e., IL-8 in human), but it also enhanced IL-3 production compared to vehicle-treated controls. Mice treated with CIP displayed a greater repopulation of bone marrow cells. CIP also limited CI-induced apoptosis and autophagy in ileal villi, systemic bacterial infection, and IgA production. CIP treatment led to LD(0/10) compared to LD(20/10) for vehicle-treated group after CI. Given the multiple beneficial activities of CIP shown in our experiments, CIP may prove to be a useful therapeutic drug for CI

Friend or Foe? IFNγ Mediates Pro-Metastatic Gene Expression in the Tumor Microenvironment (48.34)

Abstract Several immunotherapeutic models have shown that interferon gamma (IFNγ) is required for tumor regression. Treatment with IFNγ as a sole therapy, however, has resulted in disappointing outcomes. Cytokine therapies, such as IL-2/IL-12 and IL-12/IL-18, each involves IFN-γ mediated reduction in primary tumors but they can have an unanticipated increase in secondary metastases. Therefore, tumor responsiveness to IFNγ may alter its progression and metastasic potential. Mouse renal carcinoma cells expressing a dominant negative IFNγ-receptor had a reduced ability to metastasize, suggesting that IFNγ may exert potentially pro-metastatic effects in the tumor microenvironment. The goal of this study is to identify changes in gene expression in the tumor microenvironment in response to IFNγ treatment. Using qPCR gene profiling, we identified the increased expression of several pro-metastatic genes specifically in the tumor microenvironment after IFNγ treatment, namely heparanase, CD44, s100a4, and matrix metalloproteinase 7. We are now investigating whether the upregulation of these genes is caused by host and/or tumor responses to IFNγ. Our results suggest that IFNγ regulates extra-cellular matrix remodeling protein expression in the local microenvironment, which may contribute to tumor metastases.</jats:p

CIP inhibited the CI-induced increase in RelA expression after CI.

<p>On day 10 after CI, ileal samples were collected from surviving mice and prepared for immunofluorescent staining on frozen sections. RelA expression was detected (green) and presented with nucleus (blue). Representative pictures are shown with their fluorescence intensities for green signals (bottom). n = 4−5 per group. CI: combined injury; CIP: ciprofloxacin; Veh: vehicle.</p

CIP altered cytokine and chemokine profiles in serum of CI-mice.

<p>On day 10 after CI, whole blood was collected from surviving mice and the sera were separated. Sera were tested for their cytokine and chemokine concentrations. n = 3−5 per group; For A-G, *<i>p</i><0.05 vs. sham-Veh, sham-CIP, and CI+CIP; **<i>p</i><0.05 vs. sham-Veh, sham-CIP, and CI-Veh; for H-N, *<i>p</i><0.05 vs. sham-Veh and sham-CIP; for O-S, *<i>p</i><0.05 vs. sham-Veh, sham-CIP, and CI-Veh. CI: combined injury; CIP: ciprofloxacin; Veh: vehicle.</p