[Estimation of magnetic radiation effects on leucocytes]. / Ocena skutków oddzialywania promieniowania magnetycznego na leukocyty.

A lot of epidemiological and experimental research has been done recently into effects of magnetic fields (MF) on live bodies. Among others, the effects of MF on human immunological system are studied. Primary cells of the immunological system are leucocytes. A reduction of leucocyte count and any changes in their activity may lead to disturbances in the immunological system and growth of neoplasm. This paper presents a review of research into the effects of magnetic radiation on leucocytes. It describes, among other things, the influence of MF on leukocyte count changes, leucocyte cellular cycles, chromosome defects and DNA synthesis disorders in leucocytes. There is a lot of discrepancy in literature and at this stage it is difficult to draw consistent conclusion as regards the health effects of MF. Some papers claim that MF may reduce the number of leukocytes and modify their proliferation processes. In addition, there is some risk (although small) that MF will cause the aberration of the leukocyte chromosomes. As a result of leukocytes exposure to MF micronuclei were found in them, as well as changes in the activity of cytokines and natural killer cells. Considering that papers published so far present largely varied results, it is difficult to formulate solid conclusions about MF negative effects.

Sunscreens with an absorption maximum of > or =360 nm provide optimal protection against UVA1-induced expression of matrix metalloproteinase-1, interleukin-1, and interleukin-6 in human dermal fibroblasts.

UVA1-induced expression of matrix metalloproteinase-1 (MMP-1) is mediated by an autocrine mechanism involving the cytokines interleukin-1 and -6 (IL-1 and IL-6). The subsequent degradation of collagen fibers is thought to be the main cause of skin wrinkling. As it is currently not known which wavelengths within the UVA1 range are responsible for these effects, we have assessed 5 UVA1 filters (experimental filters HRH21328 and HRH22127, butyl methoxydibenzoylmethane (BMDM), diethylaminohydroxybenzylbenzoic acid hexyl ester (DHBB) and anisotriazine) with different absorption maxima for their capacity to protect against UVA1-induced MMP-1 expression. To test the efficacy of these hydrophobic filters in a cell culture system, UVA1 irradiation of primary human fibroblasts was performed through a quartz microplate filled with ethanolic solutions of the UVA filters placed on top of the cell microplate. Inhibition of UVA1-induced gene expression was detected by real time RT-PCR. The efficacy to protect against UVA1-induced MMP-1 expression was wavelength dependent: the protection by HRH22127 was best, followed by HRH21328, DHBB, BMDM, and anisotriazine. In addition, HRH22127 and HRH 21328 both significantly inhibited UVA1-induced expression of IL-1alpha and IL-6 with HRH21238 being superior to HRH22127. These studies indicate that UVA1 filters with a maximum absorption at > or =360 nm are most effective in preventing UVA1 radiation-induced MMP-1, IL-1alpha, and IL-6 expression pointing towards a critical role for effective filtering beyond > or =360 nm for protection against UVA1-induced photoaging.

Circulating leukocyte and cytokine responses to measles and poliovirus vaccination in children after ultraviolet radiation exposures.

Suberythemal ultraviolet radiation (UVR) exposures of children are used routinely in Russia to prevent rickets and to strengthen general health. The aim of the present study was to re-evaluate the effects of such a regime on immune responses as UVR is now recognised to suppress cell-mediated immunity in many animal models. Seventeen infants were immunised with attenuated measles and recall polio vaccines of whom 10 had been given a course of prophylactic UV exposures before the vaccinations. All the infants in the study developed an acute infectious conjunctivitis one week prior to the vaccinations and were convalescent at the time of the vaccination. They were bled on the day of the vaccinations and at several times thereafter to assess leukocyte percentages and plasma cytokine levels. On the day of the vaccinations, an active immune response was apparent. The UV-exposed children differed from the unexposed children by having a smaller percentage of natural killer cells and a higher percentage of CD25-positive cells. In the days following the vaccinations, the UV-exposed infants had a lowered percentage of total lymphocytes with increased percentages of monocytes, eosinophils, neutrophils and HLA-DR-positive cells as well as higher concentrations of plasma IL-1beta and IL-10 compared with the unexposed infants. There were no local or systemic clinical reactions to the vaccines in the UV-group while a moderate rise in temperature of three children in the unexposed group occurred. Thus the UV irradiations modulated leukocyte percentages and plasma cytokine levels following the vaccinations, perhaps through the activation of a T helper 2-like response.

Solar-simulated irradiation evokes a persistent and biphasic IL-1alpha response.

Exposure of skin to solar-simulated irradiation generates a multitude of adaptive responses including cytokine transcription, synthesis and secretion. Interleukin-1 (IL-1) is one of the cytokines induced in epidermal cells in response to UV irradiation. It displays a broad range of mitogenic and inflammatory activities including fibroblast proliferation and T-cell activation. There are two forms, IL-1alpha and IL-1beta; and IL-1alpha is the predominant form secreted by epidermal keratinocytes. UV-induced modulations of IL-1alpha message levels have been extensively studied within the first 48 h after irradiation, but longer term changes and impact on IL-1alpha cellular protein levels are virtually unexplored. We now report that cells of keratinocyte origin (SCC 12F) respond to a single physiologic dose of solar-simulated irradiation with both early (8 h) and late (72 h) peaks of IL-1alpha mRNA induction. UV-stimulated IL-1alpha secretion is increased above sham-irradiated control secretion for at least 96 h after irradiation. Our study provides evidence that UV-induced adaptive cutaneous responses persist for at least several days, and suggests that different mechanisms may mediate the early vs. late inductions.

Ultraviolet B radiation-induced cell death: critical role of ultraviolet dose in inflammation and lupus autoantigen redistribution.

The nuclear self-Ags targeted in systemic lupus erythematosus translocate to the cell membrane of UV-irradiated apoptotic keratinocytes and may represent an important source of self-immunization. It is hard to understand how the noninflammatory milieu accompanying most apoptosis might provoke an immunogenic response leading to autoantibodies. We have found that the precise amount of keratinocyte UV exposure is crucial in determining the rate of apoptosis, the amount of inflammatory cytokine production, and the degree of autoantigen translocation. Low doses of UVB (

Analysis of interleukin-1 beta-induced cell signaling activation in rat hippocampus following exposure to gamma irradiation. Protective effect of eicosapentaenoic acid.

Among the many reported effects of irradiation in cells is activation of the stress-activated protein kinase, c-Jun N-terminal kinase (JNK), which has been shown to result in apoptotic cell death. The trigger that leads to JNK activation has not been identified, although, in rat hippocampus at least, irradiation-induced apoptosis has been coupled with increased accumulation of reactive oxygen species (ROS). Significantly, irradiation-induced changes in hippocampus are abrogated by treatment of rats with the polyunsaturated fatty acid, eicosapentaenoic acid (EPA). A close coupling between ROS accumulation and concentration of the pro-inflammatory cytokine, interleukin-1 beta (IL-1 beta) in hippocampus has been reported, and the evidence suggests that IL-1 beta may be responsible for the enhanced ROS production. Here we set out to assess the possibility that whole body gamma-irradiation increases IL-1 beta concentration in hippocampus and to investigate the consequences of such a change. We present evidence that reveals that the irradiation-induced increase in IL-1 beta concentration in hippocampus is accompanied by increased expression of IL-1 type I receptor and IL-1 accessory protein and increased activation of IL-1 receptor-activated kinase. These changes, which were coupled with increased activation of JNK and evidence of apoptotic cell death, were absent in hippocampus of rats that received EPA treatment. Significantly, EPA treatment enhanced hippocampal IL-10 concentration that was inversely correlated with IL-1 beta concentration. The data are consistent with the idea that EPA exerts anti-inflammatory and neuroprotective effects in the central nervous system.

Histochemical and biochemical modifications induced by experimental irradiation of human skin maintained in survival conditions and modulation by application of an emulsion containing trolamine.

Radiotherapy continues to cause skin disorders. In this article, with the aid of our human skin model maintained in ex vivo survival conditions for 15 days, we describe the modifications caused by irradiation and their modulation by a trolamine-containing emulsion (Biafine). Normal human skin fragments were maintained in organ culture. One ionizing radiation session with 5 Gy was applied. Skin parameters were evaluated 24 h after the radiation session and were compared with a nonirradiated skin fragment: vascular modifications (histology), edema, epithelial proliferation, interleukin (IL)-1alpha and IL-6. Another series of skin fragments was maintained in survival conditions for 15 days after the radiation session to evaluate collagen neosynthesis by fibroblasts and any vascular changes (CD34). After irradiation the basal cell proliferation was reduced by approximately 50%. Extensive vasodilation occurred with altered capillary permeability accompanied by decreased CD34 transmembrane protein expression. Collagen synthesis and IL-1 secretion were increased. Biafine significantly reduced capillary alterations, restored CD34 expression as well as epithelial cell proliferation and significantly decreased collagen synthesis and IL-1 expression. With this ex vivo human skin model we confirmed the main modifications induced by radiotherapy as previously described in animal models: decreased basal cell proliferation and endothelial cell alterations and increased collagen synthesis by fibroblasts, probably under the influence of IL-1. The effect of Biafine emulsion on these histological and biochemical parameters may support its clinical efficacy.

UV light synergistically enhances the cardiotoxic effects of interleukin 1beta through peroxynitrite formation.

BACKGROUND: Proinflammatory cytokines play an important role in chronic cardiac diseases. METHODS AND RESULTS: Neonatal rat cardiomyocytes were exposed to interleukin (IL)-1beta (2 ng/mL) for 4 days. We assessed contractility through videomicroscopy and calcium transients with the Ca(2+)-sensitive dye fura-2. In IL-1beta-treated cells, the UV excitation (380 nm) necessary to induce dye fluorescence effected a rapid cessation of Ca(2+) transients and contraction, accompanied by calcium overload originating from an intracellular compartment. This occurred in the absence of fura-2 but required UV illumination. Incubation with 10 mmol/L N-acetylcysteine prevented this response, suggesting a free radical-mediated event. However, exposure to IL-1beta either increased or did not change the activity of the free radical scavengers superoxide dismutase, catalase, and glutathione peroxidase. In contrast, lipid peroxidation increased by 600% (P < or =.0001) in the IL-1beta plus UV-treated cells, an effect eliminated by L-NMMA. L-NMMA also completely abolished the UV-mediated cytotoxicity. We used immunohistochemistry to localize nitrotyrosine accumulation in the myocytes cotreated with IL-1beta and UV, an effect that was also blocked by L-NMMA. CONCLUSIONS: We hypothesize that the toxic radical peroxynitrite, arising from nitric oxide and superoxide anion, may be responsible for tetany and acute cardiomyocyte death. These results demonstrate the potential role of peroxynitrite in cardiotoxicity, which may be important in cardiac diseases associated with proinflammatory cytokines.

Timecourse study of UVB-induced cytokine induction in whole mouse skin.

Ever since the skin was recognized as a site of immunologic activity, a number of laboratories have studied the production of cytokines by skin cells and the effects of chemicals, allergens, contact irritants and UVB radiation on their production. Most research to date has been carried out using either purified populations of primary cells, or established cell lines. Cytokines, however, do not function in isolation but they appear in human tissues within the context of other cytokines that can, in turn, strongly influence the final biological outcome. Therefore, in vivo studies using whole skin are more physiologically relevant since all cell types are present and interactions among them are allowed to proceed. We report here the results of a detailed timecourse study using whole mouse skin, consisting of both dermis and epidermis, irradiated with either a low or high dose of UVB and analyzed using a Multi-probe RNase protection assay system. The results show that in whole skin the kinetics of cytokine induction are different than what was previously observed in tissue culture. In addition to already known skin-associated cytokines, we report here the presence and UVB induction of cytokines not previously reported.

Rapid induction of cytokine gene expression in the lung after single and fractionated doses of radiation.

PURPOSE: To investigate cytokine gene expression in the lung after single and fractionated doses of radiation, and to investigate the effect of steroids and the genetic background. MATERIALS AND METHODS: Expression of cytokine genes (mTNF-alpha, mIL-1alpha, mIL-1beta, mIL-2, mIL-3, mIL-4, mIL-5, mIL-6, mIFN-gamma) in the lungs of C3H/HeJ and C57BL/6J mice was measured by RNase protection assay at different times after various doses of radiation. The effects of dexamethasone and fractionated radiation treatment on gene expression were also studied. RESULTS: IL-1beta was the major cytokine induced in the lungs of C3H/HeJ mice within the first day after thoracic irradiation. Radiation doses as low as 1 Gy were effective. Responses to 20 Gy irradiation peaked within 4-8h and subsided by 24 h. With the exception of IL-1alpha and TNF-alpha, the other cytokines that were investigated had undetectable pre-treatment mRNA levels and were not radiation inducible. Similar responses were seen in C57BL/6J mice, although TNF-alpha was induced and there were some quantitative differences. Pre-treatment of C3H/HeJ mice with dexamethasone reduced basal and induced IL-1 levels, but complete inhibition was not achieved. Dexamethasone was also effective if given immediately after irradiation. Fractionated daily doses of radiation (4 Gy/day) helped to maintain cytokine gene expression for a longer period. CONCLUSIONS: Inflammatory genes are rapidly induced in the lung by irradiation. This response cannot be readily abolished by steroid pre-treatment. Fractionated treatment schedules help to perpetuate the response.

Manganese [correction of Magnesium] superoxide dismutase (MnSOD) plasmid/liposome pulmonary radioprotective gene therapy: modulation of irradiation-induced mRNA for IL-I, TNF-alpha, and TGF-beta correlates with delay of organizing alveolitis/fibrosis.

Radiation pneumonitis remains a critical dose-limiting toxicity of total body irradiation (TBI) for use in bone marrow transplantation. The acute and chronic phases of radiation damage in the mouse lung have been shown to correlate with mouse strain genotype and are dependent on fraction size, total dose, and total lung volume. Our prior studies demonstrated effective prevention of irradiation-induced lung damage and improved survival in C57BL/6J mice by MnSOD plasmid/liposome gene therapy. In the present studies, we investigated the kinetics of irradiation-induced upregulation of mRNA for acute phase cytokines interleukin (IL)-1 and tumor necrosis factor (TNF)-alpha, and fibrosis-associated transforming growth factor (TGF)-beta and isoforms (TGF-beta1, TGF-beta2 and TGF-beta3) in 2000 cGy whole-lung irradiated C57BL/6J mice, a strain known to develop dose and volume-dependent organizing alveolitis/fibrosis. The results demonstrate increase in mRNA for IL-1 between days 1 and 14 after irradiation with return to baseline levels out to 120 days. TNF-alpha mRNA levels were not initially elevated but increased between 80 and 100 days and then decreased by 120 days. The mRNA levels for TGF-beta1 demonstrated an initial increase within the first 14 days after total lung irradiation with a decrease to baseline levels out to 100 days. Then, in striking contrast to the other two cytokines, an increase in TGF-beta2 mRNA occurred at around 120 days and correlated with the detection of organizing alveolitis/radiation fibrosis and mortality. These results are consistent with a two-phase mechanism in the molecular pathology of irradiation lung injury, in which IL-1 cytokine mRNA levels correlated with the acute pneumonitis phase and delayed elevation of TNF-alpha (80-100 days), TGF-beta1 (100 days), and TGF-beta2 (120 days) were associated with the fibrosis phase. Insight into the cell-specific and tissue-specific molecular mechanisms of ionizing irradiation induction of mRNA for pulmonary cytokines may provide new strategies for treatment of radiation pneumonitis in TBI patients.

Radiation effect on rat Sertoli cell function in vitro and in vivo.

PURPOSE: To investigate the response of Sertoli cell function to 60Co gamma-rays. MATERIALS AND METHODS: Rat Sertoli cells were exposed in vitro and in vivo to 60Co gamma-rays in the dose range 3 Gy to 48 Gy and at 3 Gy and 6 Gy respectively. Cell viability and transferrin and IL-6 production were measured at different times following irradiation. RESULTS: This study confirms the resistance of in vitro irradiated rat Sertoli cells in the dose range 3 Gy to 48 Gy in terms of cell number. Radiation had no effect on the IL-1 activity of Sertoli cells. However, the experiments show that despite the absence of a macroscopic effect, Sertoli cells respond to ionizing radiation by increasing transferrin secretion, transferrin response to (Bu)2cAMP stimulation and IL-6 activity. CONCLUSIONS: Transferrin is involved in the transport of iron into germ cells and in cell differentiation. IL-6 is a potent inhibitor of meiotic DNA synthesis. Radio-induced transferrin and IL-6 could play a role in the protection of germ cells and could explain, in part, the resistance of Sertoli cells to radiation.

Pulsed electromagnetic fields enhance the induction of cytokines by peripheral blood mononuclear cells challenged with phytohemagglutinin.

We evaluated the effects of a 50-Hz pulsed electromagnetic field on the production of cytokines by both resting and mitogen-treated peripheral blood mononuclear cells. Our results demonstrate that after exposure of normal cells to EMFs for 12 h, the levels of neither interleukin-1beta, nor interleukin-2 were increased. Indeed, the concentration of tumor necrosis factor alpha decreased significantly immediately after the exposure period. The results were, however, markedly different when cells were stimulated with phytohemagglutinin immediately before the exposure to EMFs. In this case the levels of cytokines, measured 24 and 48 h after the treatment, were 630 +/- 440 pg/ml and 910 +/- 530 pg/ml for interleukin-1beta, 530 +/- 330 pg/ml, and 860 +/- 560 pg/ml for tumor necrosis factor alpha, respectively. These values were significantly higher (P < 0.05) when compared with the controls. Interleukin-2 levels were significantly higher at the end of the EMF exposure only in supernatants of phytohemagglutinin-stimulated cells and, as a consequence of this increase, the proliferation indexes also were significantly increased 48 h after the EMFs' treatment. The comparison between biological activity and the cytokine antigen present in our samples indicated that the amount of antigen was paralleled by an equal recovery of biological activity. This suggests either the absence of qualitative differences in these proteins or the impairment of both the transcriptional and translational processes.

GM-CSF production by epithelial cell line: upregulation by ultraviolet A.

It was demonstrated that UVB increases synthesis and expression of IL-1 alpha and GM-CSF by keratinocytes. Upregulation of GM-CSF by UVB is reported to be mediated by IL-1 alpha. However, regulation of IL-1 alpha and GM-CSF by UVA is not well-known. The purpose of the present study was to evaluate the effects of UVA on IL-1 alpha and GM-CSF production. Here we used a competitive RT-PCR for measuring cytokine gene expression in an epidermal cell line after UVA irradiation. IL-1 alpha and GM-CSF mRNA did not show any change at 1 h and 6 h following exposure to UVA. After UVA irradiation, however, IL-1 alpha mRNA decreased and GM-CSF mRNA increased at 24 h and the level of GM-CSF in culture supernatant increased at 24 h and 48 h. Addition of antihuman IL-1 alpha neutralizing antibody to UVA irradiated cells did not prevent the increase of GM-CSF mRNA expression. These results suggest that UVA radiation may induce GM-CSF production through an IL-1 alpha independent pathway.

Epidermal stratification reduces the effects of UVB (but not UVA) on keratinocyte cytokine production and cytotoxicity.

Ultraviolet (UV) radiation induces cytokine release from cultured keratinocytes as well as from epidermis in vivo. The purpose of this study was to determine whether differentiation of cultured keratinocytes into stratified epithelium decreases the effects of UVA and UVB radiation on cytokine release. Interleukin-1 (IL-1) alpha, IL-1 beta and tumor necrosis factor (TNF)-alpha release from human keratinocytes and reconstituted human epidermis was measured after exposure to UVA or UVB radiation. Release of IL-1 alpha, IL-1 beta, and TNF-alpha was induced by both UVA and UVB radiation from both keratinocytes and reconstituted epidermis. Release of these cytokines was correlated with cytotoxicity. Keratinocyte cultures were far more sensitive to UVB radiation than reconstituted epidermis, in terms of both cytotoxicity and cytokine release. In contrast, epidermal stratification/differentiation had much less effect on the sensitivity to UVA radiation. We conclude that epidermal stratification and the formation of a stratum corneum provide protection against UVB radiation but have limited barrier effect against UVA radiation.

Penetration of keratinocyte-derived cytokines into basement membrane.

Keratinocytes are known to produce a wide variety of cytokines which are believed to play a significant role in cutaneous inflammatory and immunologic reactions. Considering the array of proteolytic enzymes present in the skin and the transient nature of cytokines produced from keratinocytes, it is unclear whether cytokines released by keratinocytes cross the basement membrane and contribute to distal inflammatory and immune reactions. To investigate the ability of cytokines released from human keratinocytes to cross basement membrane, we used a two chamber culture model. Keratinocytes were plated in the upper chamber coated with a reconstituted basement membrane matrix (matrigel) on a microporous membrane. To augment cytokine production, we exposed keratinocytes to 300 J/m2 UVB; 24 h later the supernatants were collected, and the levels of cytokine were measured by ELISA. IL-1alpha, IL-6, and TNF-alpha were found to be increased after UVB irradiation in the upper chamber, and significant amounts (70-80%) of each cytokine were detected in the lower chamber. Our results indicate that keratinocyte-derived cytokines are available for interactions below the basement membrane and present circumstantial evidence that the production of those cytokines from keratinocytes contributes to the elevation of circulation after the UVB exposure.

Differences in responses of interleukin-1 and tumor necrosis factor alpha production and secretion to cyclosporin-A and ultraviolet B-irradiation by normal and transformed keratinocyte cultures.

Among epidermal cytokines, IL-1 and TNF alpha are involved in inflammatory skin reactions and suspected of modulation by immunosuppressive treatment (e.g., cyclosporin A, CsA) or UVB-irradiation, 2 mediators probably being involved in epithelial carcinogenesis. We evaluated the effects of 8 micrograms/ml CsA and 100 J/m2 UVB-irradiation on the production and secretion of IL-1 and TNF alpha on normal human epidermal keratinocytes (NHK) and epidermal keratinocyte cell lines either spontaneously transformed (HaCaT) or transformed by human papillomavirus (HPV) type 16 or 18 (EK 16 and EK18), by using ELISA test. Normal and immortalized keratinocytes constitutively produced and released IL-1 alpha, IL-1 beta and IL-1 receptor antagonist (IL-1RA) but IL-1 synthesis by NHK was significantly higher than by cell lines. All the cells spontaneously excreted low amounts of TNF alpha. Different responses to treatments were evidenced between NHK and cell lines. CsA modified significantly the production and secretion of IL1 in most cells whereas slight changes were observed with TNF alpha secretion. UVB irradiation had no effect on the intracellular IL1 pool of any cells but increased the release of IL1 and TNF alpha. The association CsA-UVB did not result in additive effects on synthesis and secretion of IL1; the release of TNF alpha by the cells remained poor except for EK18 cells. Taken together, these results show that, in immortalized keratinocytes, the IL-1 and TNF alpha expression was differently affected by treatments with CsA and/or UVB-irradiation as compared to NHK. In addition, spontaneously transformed keratinocytes, HaCaT, reacted differently from HPV-transformed keratinocytes, EK16 and EK18.

High and low dose rate irradiation have opposing effects on cytokine gene expression in human glioblastoma cell lines.

Effects of radiation on five cytokine expressing human glioblastoma cell lines were studied. In comparison to unirradiated controls, IL-1 beta and IL-6 mRNAs were generally reduced after low (LDR, 1.0 cGy/min) and very low (VLDR, 0.35 cGy/min) dose rate irradiation. In contrast, high (HDR, 200 cGy/min) and intermediate (IDR, 4.1 cGy/min) dose rates increased steady-state levels of IL-1 beta and IL-6 mRNAs. The surviving fraction was generally inversely proportional to the dose rate; however, these glioma cells were unusually susceptible to LDR. In the two cell lines tested, IDR was less cytotoxic than either HDR or LDR irradiation. Although cytokine gene expression had no clear effect on radiation survival in vitro, autologous cytokines could be important to radiation response in vivo by affecting immune response, tumour stroma, vasculature or surrounding tissues. Adjusting dose rates to account for inverse dose rate effects and altered gene expression may be a useful strategy in optimising radiation therapy of glioblastomas.

Induction of acute phase gene expression by brain irradiation.

PURPOSE: To investigate the in vivo acute phase molecular response of the brain to ionizing radiation. METHODS AND MATERIALS: C3Hf/Sed/Kam mice were given midbrain or whole-body irradiation. Cerebral expression of interleukins (IL-1 alpha, IL-1 beta, IL-2, IL-3, IL-4, IL-5, IL-6), interferon (IFN-gamma), tumor necrosis factors (TNF-alpha and TNF-beta), intercellular adhesion molecule-1 (ICAM-1), inducible nitric oxide synthetase (iNOS), von Willebrand factor (vWF), alpha 1-antichymotrypsin (EB22/5.3), and glial fibrillary acidic protein (GFAP) was measured at various times after various radiation doses by ribonuclease (RNase) protection assay. The effects of dexamethasone or pentoxifylline treatment of mice on radiation-induced gene expression were also examined. RESULTS: Levels of TNF-alpha, IL-1 beta, ICAM-1, EB22/5.3 and to a lesser extent IL-1 alpha and GFAP, messenger RNA were increased in the brain after irradiation, whether the dose was delivered to the whole body or only to the midbrain. Responses were radiation dose dependent, but were not found below 7 Gy; the exception being ICAM-1, which was increased by doses as low as 2 Gy. Most responses were rapid, peaking within 4-8 h, but antichymotrypsin and GFAP responses were delayed and still elevated at 24 h, by which time the others had subsided. Pretreatment of mice with dexamethasone or pentoxifylline suppressed radiation-induced gene expression, either partially or completely. Dexamethasone was more inhibitory than pentoxifylline at the doses chosen. CONCLUSIONS: The initial response of the brain to irradiation involves expression of inflammatory gene products, which are probably responsible for clinically observed early symptoms of brain radiotherapy. This mechanism explains the beneficial effects of the clinical use of steroids in such circumstances.