Pro- and anti-inflammatory cytokines regulate the ERK pathway: Implication of the timing for the activation of microglial cells
Pro- and anti-inflammatory cytokines regulate the ERK pathway: Implication of the timing for the activation of microglial cells
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DOI：
10.1007/bf03033981
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发表时间：
2005-11-01
影响因子：
3.7
通讯作者：
Von Bernhardi, R
中科院分区：
文献类型：
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作者：
Saud, K;Herrera-Molina, R;Von Bernhardi, R
促炎分子诱导胶质细胞活化并释放能够产生氧化损伤的潜在有害因子，如一氧化氮（NO）和超氧阴离子（O-2）。活化的胶质细胞（星形胶质细胞和小胶质细胞）与神经退行性疾病的炎症过程有关。强烈的炎症反应可以逃避内源性控制，对神经元产生毒性，并促进疾病的发展。我们在海马细胞-小胶质细胞共培养模型中评估了由脂多糖+干扰素- γ (LPS+ ifn - γ)诱导的促炎状态是否直接促进了损伤，或者损伤是否继发于胶质细胞激活。此外，我们还探讨了抗炎细胞因子转化生长因子- β 1（tgf - β 1）、促炎细胞因子白介素-1 β (IL-1 β)和肿瘤坏死因子- α (tnf - α)对小胶质细胞炎症反应的调控作用。我们发现LPS+ ifn - γ诱导的海马培养损伤依赖于小胶质细胞的存在。在暴露于LPS+ ifn - γ的海马培养物中，tgf - β 1被诱导，而在小胶质细胞培养物中，LPS+ ifn - γ诱导分泌IL-1 β。tgf - β 1和IL-1 β使一氧化氮生成减少70-90%，而tnf - α没有作用。MAP激酶（MEK）抑制剂PD98059可使ifn - γ诱导的NO生成减少40%。tgf - β 1和IL-1 β分别使ifn - γ诱导的ERK1,2磷酸化降低60%和40%。然而，IL-1 β的影响在暴露30分钟后观察到，tgf - β 1仅在暴露24小时后观察到。我们提出，tgf - β 1和IL-1 β可以通过不同的时间调节细胞外信号调节激酶ERK1,2，作为不同转导途径的共同元件，调节胶质细胞对LPS+ ifn - γ的激活幅度和持续时间。脑细胞间的串扰可能是理解神经退行性疾病发病机制中涉及的炎症机制的关键。
Pro-inflammatory molecules induce glial activation and the release of potentially detrimental factors capable of generating oxidative damage, such as nitric oxide (NO) and superoxide anion (O-2(.-))Activated glial cells (astrocytes and microglia) are associated to the inflammatory process in neurodegenerative diseases. A strong inflammatory response could escape endogenous control becoming toxic to neurons and contributing to the course of the disease. We evaluated in a hippocampal cells-microglia co-culture model, if the pro-inflammatory condition induced by lipopolysaccharide + interferon-gamma (LPS+IFN-gamma) promoted damage directly or if damage was secondary to glial activation. In addition, we explored the effect of the antiinflammatory cytokine transforming growth factor-beta 1(TGF-beta 1), and pro-inflammatory cytokines, interleukin-1 beta (IL-1 beta) and tumor necrosis factor-alpha (TNF-alpha) on the regulation of the inflammatory response of microglia. We found that LPS+IFN-gamma-induced damage on hippocampal cultures was dependent on the presence of microglial cells. In hippocampal cultures exposed to LPS+IFN-gamma, TGF-beta 1 was induced whereas in microglial cell cultures LPS+IFN-gamma induced the secretion of IL-1 beta. TGF-beta 1 and IL-1 beta but not TNF-alpha decreased the NO production by 70-90%. PD98059, an inhibitor of MAP kinase (MEK), reduced the IFN-gamma-induced NO production by 40%. TGF-beta 1 and IL-1 beta reduced the IFN-gamma-induced phosphorylation of ERK1,2 by 60% and 40%, respectively. However, the effect of IL-1 beta was observed at 30 min and that of TGF-beta 1 only after 24 h of exposure. We propose that acting with different timing, TGF-beta 1 and IL-1 beta can modulate the extracellular signal-regulated kinase ERK1,2, as a common element for different transduction pathways, regulating the amplitude and duration of glial activation in response to LPS+IFN-gamma. Cross-talk among brain cells may be key for the understanding of inflammatory mechanisms involved in pathogenesis of neurodegenerative diseases.