McBride, W. H., Chiang, C-S., Olson, J. L., Wang, C-C., Hong, J-H., Pajonk, F., Dougherty, G. J., Iwamoto, K. S., Pervan, M. and Liao, Y-P. A Sense of Danger from Radiation. Radiat. Res. 162, 1–19 (2004).Tissue damage caused by exposure to pathogens, chemicals and physical agents such as ionizing radiation triggers production of generic “danger” signals that mobilize the innate and acquired immune system to deal with the intrusion and effect tissue repair with the goal of maintaining the integrity of the tissue and the body. Ionizing radiation appears to do the same, but less is known about the role of “danger” signals in tissue responses to this agent. This review deals with the nature of putative “danger” signals that may be generated by exposure to ionizing radiation and their significance. There are a number of potential consequences of “danger” signaling in response to radiation exposure. “Danger” signals could mediate the pathogenesis of, or recovery from, radiation damage. They could alter intrinsic cellular radiosensitivity or initiate radioadaptive responses to subsequent exposure. They may spread outside the locally damaged site and mediate bystander or “out-of-field” radiation effects. Finally, an important aspect of classical “danger” signals is that they link initial nonspecific immune responses in a pathological site to the development of specific adaptive immunity. Interestingly, in the case of radiation, there is little evidence that “danger” signals efficiently translate radiation-induced tumor cell death into the generation of tumor-specific immunity or normal tissue damage into autoimmunity. The suggestion is that radiation-induced “danger” signals may be inadequate in this respect or that radiation interferes with the generation of specific immunity. There are many issues that need to be resolved regarding “danger” signaling after exposure to ionizing radiation. Evidence of their importance is, in some areas, scant, but the issues are worthy of consideration, if for no other reason than that manipulation of these pathways has the potential to improve the therapeutic benefit of radiation therapy. This article focuses on how normal tissues and tumors sense and respond to danger from ionizing radiation, on the nature of the signals that are sent, and on the impact on the eventual consequences of exposure.

Gliosis is a characteristic pathologic state in many CNS disorders. Cytokines are considered to be effectors of gliosis. In order to explore the role of IL-6 in gliosis, the temporal and spatial expression of the IL-6 gene and its consequent effects on the brain were studied in a GFAP-IL6 transgenic mouse model. In GFAP-IL6 mice, IL-6 transgene expression was detectable in the brain at 1 week postnatally and increased to maximal levels by 3 months of age before declining at 8 and 12 months. Enhanced glial fibrillary acidic protein (GFAP) (marker for astrocytes) and Mac-I (marker for microglia) mRNA expression were first prominent at 1 month, increased to maximum levels by 3 months and remained significantly elevated through 12 months of age. Western blot analysis revealed that the enhanced GFAP mRNA expression in these transgenic mice was accompanied by increased GFAP protein levels. Immunostaining for Mac-I demonstrated that in addition to an increased staining intensity, the number of cells expressing the microglial/macrophage marker was also apparently increased, particularly in the cerebellum and brain stem. Concurrent with IL-6 transgene mRNA expression and reactive gliosis, upregulation of IL-1α/β, TNFα, ICAM-1 and EB22/5.3 (acute-phase reactant) but not inducible nitric oxide synthase gene expression was also observed. EB22/5.3 mRNA expression was most prominent and increased progressively with age. Expression of the IL-6, GFAP and EB22/5.3 RNAs was found to have similar distribution in the brain being found predominantly in the cerebellum, brain stem and sub-cortical regions. In conclusion, the constitutive expression of IL-6 in the brain induced the development of a pronounced and lifelong reactive gliosis affecting both astrocytes and microglia. The altered state of these cells may contribute to the functional and structural CNS impairment exhibited by the GFAP-IL6 mice. Finally, in these mice, expression of the EB22/5.3 gene correlated closely with the progression of neuropathy indicating that this acute-phase response gene was a good marker for and may be involved in the pathogenesis of CNS injury mediated by the expression of IL-6.

Macrophages display different phenotypes with distinct functions and can rapidly respond to environmental changes. Previous studies on TRAMP-C1 tumor model have shown that irradiation has a strong impact on tumor microenvironments. The major changes include the decrease of microvascular density, the increase of avascular hypoxia, and the aggregation of tumor-associated macrophages in avascular hypoxic regions. Similar changes were observed no matter the irradiation was given to tissue bed before tumor implantation (pre-IR tumors), or to established tumors (IR tumors). Recent results on three murine tumors, TRAMP-C1 prostate adenocarcinoma, ALTS1C1 astrocytoma, and GL261 glioma, further demonstrate that different phenotypes of inflammatory cells are spatially distributed into different microenvironments in both IR and pre-IR tumors. Regions with avascular hypoxia and central necrosis have CD11b^high/Gr-1+ neutrophils in the center of the necrotic area. Next to them are CD11b^low/F4/80+ macrophages that sit at the junctions between central necrotic and surrounding hypoxic regions. The majority of cells in the hypoxic regions are CD11b^low/CD68+ macrophages. These inflammatory cell populations express different levels of Arg I. This distribution pattern, except for neutrophils, is not observed in tumors receiving chemotherapy or an anti-angiogenesis agent which also lead to avascular hypoxia. This unique distribution pattern of inflammatory cells in IR tumor sites is interfered with by targeting the expression of a chemokine protein, SDF-1α, by tumor cells, and this also increases radiation-induced tumor growth delay. This indicates that irradiated-hypoxia tissues have distinct tumor microenvironments that favor the development of M2 macrophages and that is affected by the levels of tumor-secreted SDF-1α.