Ionizing Radiation Potentiates the Induction of Nitric Oxide Synthase by Interferon‐γ and/or Lipopolysaccharide in Murine Macrophage Cell Lines: Role of Tumor Necrosis Factor‐α

Abstract

A BSTRACT : Macrophages respond to infection or injury by changing from a "resting" cellular phenotype to an "activated" state defined by the expression of various cytotoxic effector functions. Regulation of the transition from a resting to an activated state is effected by cytokine and/or pathogenic signals. Some signals do not directly induce activation, but instead "prime" the macrophage to respond more vigorously to a second signal. One example of this priming phenomenon involves induction of nitric oxide (NO) synthesis by the enzyme nitric oxide synthase (NOS2). Our experiments indicate that low doses (1-5 Gy) of ionizing radiation can enhance the induction of enzymatically active NOS2 by IFN-␥ or LPS in J774.1 and RAW264.7 murine macrophage cell lines. Radiation alone did not produce this induction, rather, it was effective as a priming signal; cells exposed to radiation produced more NO when a second signal, either IFN-␥ or LPS, was applied 24 h later.

Contralateral response of macrophages and astrocytes to injury in the cerebral hemisphere of 6‐day‐old rat following prenatal gamma irradiation

“…Prenatal irradiation might intensify the cell apoptosis (Schultheiss et al, 1995) which, in turn, could activate phagocytes removing cell debris. The phagocytes could also be "primed" by prenatal irradiation and respond more vigorously to postnatal injury (McKinney et al, 1998(McKinney et al, , 2000 and produce more pro-inflammatory cytokines affecting other cell types (Ibuki and Goto, 1999;Ishihara et al, 1995).…”

Macrophage biology plays a central role during ionizing radiation-elicited tumor response

“…When irradiated at a higher dose (≥1 Gy), macrophages tend to display a pro-inflammatory phenotype. For example, irradiation at 1–5 Gy potentiated the production of iNOS and NO in IFN-γ and LPS-stimulated J774.1 and RAW264.7 macrophages [17] . Interestingly, TNF-α was involved in this boost of pro-inflammatory mediator as TNF-α blocking antibody treatment before irradiation inhibited the induction of NO by IFN-γ [18] .…”

The potential of radiotherapy to enhance the efficacy of renal cell carcinoma therapy

“…89,90 Radiotherapy is also able to prime macrophages for pro-inflammatory signaling in a dose-dependent manner, as shown by enhanced IFNg-mediated NO production and increased TLR-mediated TNF-a secretion. 91,92 Furthermore, conventional fractionated radiotherapy was observed to skew macrophage function to an antitumor mode in different murine carcinoma models 93 and both conventional and HFRT caused a significant increase of tumor-infiltrating M1 macrophages. 94 Importantly, radiotherapy was able to enhance M2 activity in C57BL/6 mice, while increasing M1 activity in CBA/CaJ mice.…”