Cytolytic cells induce HMGB1 release from melanoma cell lines
Cytolytic cells induce HMGB1 release from melanoma cell lines
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DOI：
10.1189/jlb.0306169
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发表时间：
2007-01-01
影响因子：
5.5
通讯作者：
Lotze, Michael T.
中科院分区：
文献类型：
--
作者：
Ito, Norimasa;DeMarco, Richard A.;Lotze, Michael T.
高迁移率族蛋白1（HMGB 1）是新近定义的损伤相关分子模式分子之一，由坏死细胞被动释放并由活化的巨噬细胞/单核细胞分泌。溶细胞细胞是否诱导肿瘤细胞释放HMGB 1尚不清楚。我们开发了一种高灵敏度的方法检测细胞内HMGB 1在肿瘤细胞，允许分析的类型的细胞死亡，特别是，坏死。我们用溶细胞淋巴因子激活的杀伤（LAK）细胞、肿瘤特异性溶细胞T淋巴细胞、TRAIL或颗粒酶B递送诱导黑色素瘤细胞死亡，并评估细胞内HMGB 1的保留或释放，以研究溶细胞释放HMGB 1的机制。在与IL-2激活的PBMC孵育后4 μ l和24 h内检测到黑素瘤细胞（451 Lu，WM 9）的HMGB 1释放（LAK活性）。HLA-A2和MART 1或gp 100特异性溶细胞性T淋巴细胞诱导HMGB 1从HLA-A2阳性和MART 1阳性黑素瘤细胞（FEM X）或T2细胞负载的gp 100特异性肽释放。然而，TRAIL处理诱导HMGB 1释放，并且有趣的是，这种外源性途径介导的细胞死亡被pancaspase抑制剂N-苄氧羰基-Val-Ala-Asp-fluoromethylketone阻断。相反，颗粒酶B递送不诱导HMGB 1释放。HMGB 1沿着其他细胞因子的释放，可能是肿瘤细胞内免疫紊乱的重要组成部分。这对癌症患者的免疫治疗具有重要意义。具体而言，HMGB 1可以促进愈合或免疫反应性，这取决于局部炎症反应的性质和免疫效应物的存在（或不存在）。
High mobility group box 1 (HMGB1) is one of the recently defined damage-associated molecular pattern molecules, passively released from necrotic cells and secreted by activated macrophage/monocytes. Whether cytolytic cells induce HMGB1release from tumor cells is not known. We developed a highly sensitive method for detecting intracellular HMGB1in tumor cells, allowing analysis of the type of cell death and in particular, necrosis. We induced melanoma cell death with cytolytic lymphokine-activated killing (LAK) cells, tumor-specific cytolytic T lymphocytes, TRAIL, or granzyme B delivery and assessed intracellular HMGB1 retention or release to investigate the mechanism of HMGB1 release by cytolytic cells. HMGB1 release from melanoma cells (451Lu, WM9) was detected within 4 It and 24 h following incubation with IL-2-activated PBMC (LAK activity). HLA-A2 and MART1 or gp100-specific cytolytic T lymphocytes induced HMGB1 release from HLA-A2-positive and MART1-positive melanoma cells (FEM X) or T2 cell-loaded, gp100-specific peptides. TRAIL treatment, however, induced HMGB1 release, and it is interesting that this extrinsic pathway-mediated cell death was blocked with the pancaspase inhibitor N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone. Conversely, granzyme B delivery did not induce HMGB1 release. HMGB1, along with other intracellular factors released from tumor cells induced by cytolysis, may be important components of the disordered tumor nideroemironment. This has important implications for the immunotherapy of patients with cancer. Specifically, HMGB1 may promote healing or immune reactivity, depending on the nature of the local inflammatory response and the presence (or absence) of immune effectors.