Differential Modulation on Endotoxin- and Cytokine-Induced Release of Nitric Oxide and Cytokines by Ethanol in Glial Cells

• Main Authors: Fang Yao-Ching, 方耀慶
• Other Authors: Wang Jia-Yi
• Format: Others
• Language: zh-TW
• Published: 1998
• Online Access: http://ndltd.ncl.edu.tw/handle/67609626755299000997

碩士 === 國防醫學院 === 生理學研究所 === 86 === Ethanol has long been recognized as an general immunosuppressant and a risk factor for various infectious diseases. However, the effects of ethanol on immune functions in the CNS have not been well characterized. In fact , that the brain possesses functional immunoreactive capacity has only rec ently been recognized. Glial cells, particularly astrocytes andmicroglia play central roles in immune reactions througha plethora of mediators which in teract in complex manners when the cells are activated, providing protection but at times also detriments to the cells as well as neighboring neurons. Some of the major mediators include the cytokines such as tumor necrosis factor-alpha(TNF-alpha),interleukin 1-beta (IL-beta) and interferon-gamma (IFN-gamma) which may find a common effector in nitric oxide (NO).Since glial cells, cytokines and NO have all been implicated in immune function in the CNS, the present study focused on the possible modulatory effects of ethanol on the induction of these mediators. Firstly, effects of ethanol on the production of NO by lipopolysaccharide (LPS) in glial cells were examined. Secondly, the effects of ethanol on the producion of cytokines by LPS were studied. Thirdly, the effects ofethanol on the production of NO by cytokines were followed. Fourthly, the effects of ethanol on the production of cytokines by other cytokines were examined.At the same time, we examined and compared the mechanism (signal transduction cascade) mediating the effects in1,2 and 3 parts. Primary culture of mixed glia were prepared from the cortex of neonatal (1-day-old) Sprague-Dawley rats. Formation of NO was determined by the accumulation of its stable metabolite nitrite. LPS and cytokines were used to stimulate the glial cells. The results indicated that LPS exerted concentration-response and time-dependent effects on the production of NO. While ethanol had no direct effect on NO production, ethanol suppressed LPS-stimulated production of NO, suggesting a modulatory role of ethanol in glial cells. Inhibition of tyrosine kinases and NFB were partiallyinvolved in the effect of ethanol. While LPS didstimulate the early ( 48 hr) production of TNF-alpha, IL-1 beta or INF-gamma, significant elevation of cytokine-stimulated NO release was not seen until the incubation time was prolonged to as long as 120 hrs. Ethanol also suppressed LPS-stimulated TNF-alpha and IL-1 beta , possibly through inhibiting the initial triggering mechanism. Furthermore, ethanol suppressed cytokine-induced NO production, and inhibition of NFB was again partially involved in this action. The release of TNF-and IL-1, but not INF could be stimulated by other cytokines. Ethanol significantly suppressed the stimulated release of TNF- or IL-1 frommixed glia. These results suggest a differential modulation by ethanol on direct induction of NO and production of cytokines by LPS as well as theconsequential indirect modulation on NO productionthrough changes in cytokines release.