Brain Research, 566 (1991) 265-269 ~) 1991 Elsevier Science Publishers B.V. All rights reserved. 0006-8993/91/$03.50

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BRES 17232

Radiation enhances tumor necrosis factor a production by murine brain cells Chi-Shiun Chiang and William H. McBride Department of Radiation Oncoiogy and donsson Comprehensive Cancer Center, UCLA Medical Center, Los Angeles, CA 90024.1714 (U.S.A.)

(Accepted 23 July 1991) Key words: Tumor necrosis factor; Radiation; Astrocyte; Microglial cell

Astrocytes and microglial cells cultured from murine brain were stimulated to produce tumor necrosis factor a (TNF) by exposure to fipopolysaccharide (LPS). TNF a production began within 2 h with maximum production between 4 and 8 h after stimulation. Clinically relevant low (2 Gy), but not high (8 Gy), doses of radiation significantly increased TNF production by astrocytes and microglial cells in response to LPS. The radiation effect was even more marked with multiple 2 Gy doses. TNF is cytotoxic for oligodendrocytes and for certain tumor cells. It increases vascular permeability and enhances immune responses as well as having other bioi,~gicai effects. It is conceivable that production of TNF by astrocytes and microglial cells during clinical radiation therapy might influence t'he responses of tumor and/or normal CNS tissues.

INTRODUCTION

MATERIALS AND METHODS

Tumor necrosis factor (TNF) a is an inducible multifunctional cytokine known to be involved in many aspects of immune regulation and inflammation t4. Macrophages are considered to be the major source of TNF a but production by astrocytes and microglial cells has been described recently suggesting a possible role for this molecule in normal and pathological brain responses 7't°'t3'ts. This possibility is strengthened by the findings that TNF a induces astrocytes to proliferate t7 while being directly cytotoxic for oligodendrocytes t3't6, Radiation has been shown to enhance TNF a message and/or protein production by tumor cellse and macrophages s. In this study we show that low radiation doses administered in vitro can prime astrocytes and microglia cells for TNF a production and that fractionated doses of clinical relevance have more potent effects than do large single doses. Most severe radiation-induced CNS damage, i.e. radiation necrosis, occurs several months or years after radiation treatment ts. However, changes in the blood-brain barrier permeability, edema 4, and demyelination 2 can occur early. These early effects cannot be readily explained on the basis of radiation-induced mitotic death. The results of our experiments suggest that TNF production by astrocytes and microglial cells during the course of radiotherapy may play a role.

Cell preparation

Brains from 2-day-old C3Hf/Sed/Kam mice were used to establish the primacy cultures. The culture technique has been described by McCarthy and de Vellis9. Briefly, after removal of the brain, the meninges were dissected off with fine forceps under aseptic conditions. The tissues were homogenized and passed successively through 105-1~mand 41./~m nylon meshes. Brain cells were seeded into 75-cm2 flasks to which was added RPMI.1640 medium (Gibco, Grand Island, NY) containing antibiotics and 10%, low endotoxin (

Radiation enhances tumor necrosis factor alpha production by murine brain cells.

Astrocytes and microglial cells cultured from murine brain were stimulated to produce tumor necrosis factor alpha (TNF) by exposure to lipopolysacchar...
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