脂多醣體誘導淋巴內皮細胞 IL-6 釋放之機轉   全文下載

Molecular Mechanisms in Lipopolysaccharide-Induced Interleukin 6 Release in Lymphatic Endothelial Cells

淋巴系統主要具有運送組織間液、血管外蛋白以及細胞返回血液循環的功能，不論是在正常組織或是病理情況下包括發炎、淋巴水腫或是腫瘤轉移時都可見到淋巴內皮細胞進行淋巴管新生作用而形成淋巴管，最近有研究指出淋巴管不僅調控免疫細胞的運送，淋巴管也可能直接參與發炎反應過程中。然而目前對於淋巴管的發炎反應並不清楚，本研究主要是探討革蘭氏陰性菌細胞壁成分脂多醣體是否可誘導人類淋巴內皮細胞介白素第六因子（Interleukin-6, IL-6）的釋放及其分子作用機轉。脂多醣體可顯著增加淋巴內皮細胞的IL-6釋放，利用MAPKs包括ERK, JNK和p38MAPK的專一性抑制劑可顯著抑制脂多醣體所誘導之IL-6的釋放，我們也發現脂多醣體可活化淋巴內皮細胞之ERK, p38MAPK 和 JNK，由此推測脂多醣體可能經由活化ERK, JNK, p38MAPK而誘導IL-6的釋放。報告基因的實驗結果顯示脂多醣體可增加轉錄因子NF-κB的轉錄活性，已知轉錄因子NF-κB在轉錄調控IL-6基因扮演非常重要的角色，因此由本癌就可以推測脂多醣體可能透過活化MAPKs而增加轉錄因子NF-κB的活性，最終使得淋巴內皮細胞IL-6表現以及釋放增加。因IL-6在發炎過程當中扮演非常重要角色，如果可以降低或抑制MAPKs或是轉錄因子NF-κB的活性將有助於減少淋巴內皮細胞IL-6的表現並進一步治療淋巴管相關之發炎反應。"

The lymphatic vasculature is involved in the transportation of tissue fluids, extravasated plasma proteins and cells back into blood circulation. Formation of lymphatic vessels by lymphatic endothelial cells (LECs) occurs both in normal tissues as well as in pathological processes including inflammation, lymphedema and tumor metastasis. Recent reports demonstrated that lymphatic vasculature is not just a major conduit for immune cell transport. It seems to be directly involved in both the induction and the resolution of inflammation. However, little is known about how lymphatic vessels themselves respond to inflammation. The purpose of this study was to investigate the molecular mechanism by which interleukin-6 release in LECs exposure to lipopolysaccharide (LPS), a component of the outer membrane of Gram-negative bacteria. LPS was shown to cause an increase in IL-6 release in LECs. Pharmacological inhibitors of mitogen-activated protein kinases (MAPKs), including extracellular signal-regulated kinase (ERK), p38MAPK or c-jun N-terminal kinase (JNK), significantly abrogated the LPS-induced IL-6 release. In addition, LPS was shown to activate ERK, p38MAPK and JNK in LECs, suggesting functional cross-talk. The results of reporter assay further indicated that LPS increased the transcriptional activity of NF-κB, a critical transcription factor in inducing IL-6 expression. Our data suggest that MAPKs and NF-κB activation may contribute to LPS-induced IL-6 release in LECs. Interventions of MAPKs and NF-κB signaling may be beneficial in the treatment of lymphatic-associated inflammation.