腫瘤壞死因子alpha (TNF-alpha) 具有許多生理功能，然而過量的TNF-alpha卻會造成器官的損傷。鉛與脂多醣體 (LPS) 都是環境中常見的污染物，並且均會調控TNF-alpha的表現。然而，是否這兩個環境污染物會透過交互作用而放大TNF-alpha的產量進而造成更大的影響，至今仍不清楚。本研究的目的是觀察鉛刺激TNF-alpha表現的可能訊號傳遞機制，以及此經由鉛直接刺激或增強LPS作用而過量產生的TNF-alpha，是否對器官造成傷害，藉以模擬環境因子干擾發炎反應的效應。由於神經系統是鉛中毒的標的器官，在本研究中首先以神經膠原細胞株U-373MG或B6小鼠為對象。結果顯示，單獨鉛或LPS就足以刺激神經膠原細胞表現TNF-alpha，但鉛與LPS間並無加成作用。鉛能經由PKC增加U-373MG細胞中p42/44 MAPK的磷酸化，但是不會改變I-κB的磷酸化或活化NF-κB。直接抑制MAPK或PKC的活性後，可以減少U-373MG細胞及小鼠腦部中由鉛所刺激而表現的TNF-alpha。所以鉛活化PKC-p42/44 MAPK的路徑是腦部增加TNF-alpha表現的主要訊息路徑。另一方面，由於肝臟是TNF-alpha傷害的主要標的器官，因此在接續的實驗中以肝臟傷害作為TNF-alpha作用的指標。雖然以鉛單獨處理大鼠或小鼠時，並不能刺激血中TNF-的產生，但是在合併低劑量LPS處理下，血清中少量的TNF-alpha會因為鉛的共同暴露而大量增加，並伴隨嚴重的肝臟損害。以pentoxifylline抑制TNF-alpha的基因轉錄後能降低肝臟傷害。肝臟組織並不表現TNF-alpha，但是在低劑量LPS刺激下，鉛能增強血液細胞、CD14+細胞、腹腔巨噬細胞及巨噬細胞株RAW264.7等細胞表現TNF-alpha。鉛本身只會增加少許巨噬細胞p42/44 MAPK的磷酸化，但鉛合併LPS處理後，p42/44 MAPK的磷酸化程度明顯的增強。阻斷MAPK及PKC活性後，由鉛增加LPS所刺激產生的TNF-alpha也隨之下降。總結以上的證據，PKC/MAPK是神經膠原細胞及巨噬細胞受到鉛或鉛合併LPS產生TNF-alpha的主要訊息路徑。由於免疫細胞對環境污染物的敏感，造成了多重環境污染物的暴露會借由相同訊息路徑刺激免疫細胞產生過量的TNF-alpha，進而放大其對器官的傷害。

Tumor necrosis factor-alpha (TNF-alpharegulates plenty of biological functions, including immune responses, haematopoiesis, and morphogenesis. Excessive TNF-alpha expression may cause multiple organ injury. Some of environmental pollutants may trigger TNF-alpha production; however, whether they act synergistically to amplify the harmful effects of TNF-alpha remains unclear. Lead and lipopolysaccharide (LPS) are two common environmental pollutants and can induce TNF-alpha expression. In this study, the mechanisms of lead- and LPS-regulated TNF-alpha production were characterized and the synergistic effect of lead and LPS was evaluated. Furthermore, the effects of these pollutants-induced TNF-alpha on nerve system and liver were evaluated to address the potential damages in vivo. Lead and LPS alone induced the expression of TNF-alpha in human glioma cell line U-373MG and in the glia of B6 mice. No apparent synergistic effect was observed for co-exposure of lead and LPS (Pb+LPS) regarding the TNF-alpha production and damage in cells of glia origin. In U-373MG, both lead and LPS increased the phosphorylation of p42/44 MAPK through PKC activation. Blockage of PKC or p42/44 MAPK effectively reduced the lead-induced TNF-alpha in U-373MG and glial cells in the mouse brain. Although lead and LPS could stimulate glial cells to express TNF-alpha, no cell death was observed in U-373MG and in the mouse brain. Only LPS, but not lead, induced I-κB phosphorylation and NF-κB activation for cells of glia origin. In contrast to the effects on glia, lead significantly increased the level of TNF-alpha in sera of A/J mice and rats in the present of low dose of LPS. Moreover, Pb+LPS caused profound liver injury, which could be ameliorated by inhibiting the production of TNF-alpha. Although mouse liver was severely damaged by TNF-alpha, no TNF-alpha positive cells were detected in the liver per se. Lead enhanced the low dose LPS-induced TNF-alpha expression in CD14+ cells of peripheral blood, in peritoneal macrophages, and in macrophage cell line RAW264.7. Functional inactivation of monocytes/macrophages in mice by GdCl3 significantly decreased the Pb+LPS-induced serum TNF-alpha and concurrently reduced liver injury. Pb+LPS stimulated obvious phosphorylation of p42/44 MAPK in peritoneal macrophages, being confirmed as F4/80+ cells, and in RAW264.7 cells. Pretreating inhibitors for PKC or MAPK effectively reduced the Pb+LPS-induced TNF-alpha expression in peritoneal macrophages, RAW264.7 cells, and in sera of mice and rats. Taken together, PKC/MAPK is the common signaling pathway trigged by lead and LPS to induce the expression of TNF-alpha in glial cells and macrophage/monocytes. Moreover, environmental pollutions can act synergistically and effectively on immune cells leading to sever damages in a tissue specific manner.

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