Treon S P, Broitman S A
Department of Microbiology, Boston University School of Medicine, MA 02118.
Leukemia. 1992 Oct;6(10):1036-42.
Post-transfusional hepatitis is often a complication in patients with acute myelogenous leukemia (AML) in whom survival is paradoxically prolonged. The etiology is unknown. In previous studies, we showed that impaired hepatic endotoxin (lipopolysaccharide, LPS) clearance in patients with acute viral hepatitis A, B, or C versus controls results in endotoxemia and tumor necrosis factor alpha (TNF-alpha) release. TNF-alpha mediates anti-proliferative and differentiating effects in AML cell lines. Interferon-gamma (IFN-gamma) released in acute viral hepatitis, acts in synergy with TNF-alpha. HL60, KG1, and U937 AML cells treated 3, 6, and 9 days with physiologically attainable TNF-alpha (10 U/ml), IFN-gamma (100 U/ml) and LPS (10 ng/ml) levels, have significantly diminished viability and cell growth versus controls. Treatment of HL60 AML cells with LPS/TNF-alpha/IFN-gamma also resulted in significantly increased monocytic pathway differentiation not seen with KG1 or U937 AML cells. HL60 AML cells treated with TNF-alpha/IFN-gamma for 6 days released endogenous TNF-alpha (1.57 U/10(6) cells) upon LPS stimulation compared to less than 0.01 U/10(6) cells in non-LPS-stimulated TNF-alpha/IFN-gamma-treated cells or untreated cells (p less than 0.0001). Untreated HL60 AML cells co-cultured with HL60 cells pretreated for 6 days with TNF-alpha/IFN-gamma and then subjected to LPS stimulation had significantly diminished cell growth compared to controls (p less than 0.0001). This effect could be reversed with anti-TNF-alpha antibody, supporting the concept that endogenous TNF-alpha release by LPS/TNF-alpha/IFN-gamma treated HL60 AML cells may act by paracrine means to suppress growth of other AML cells. The beneficial effects of post-transfusional hepatitis in AML patients may be mediated via LPS/TNF-alpha/IFN-gamma-induced AML cell growth suppression and/or terminal differentiation in which AML cells participate by releasing TNF-alpha after being acted upon by LPS/TNF-alpha/IFN-gamma. Endogenously released TNF-alpha might then act by autocrine/paracrine means to mediate further suppression and terminal differentiation.
输血后肝炎常是急性髓性白血病（AML）患者的一种并发症，而这些患者的生存期反而延长。其病因尚不清楚。在先前的研究中，我们发现，与对照组相比，甲型、乙型或丙型急性病毒性肝炎患者肝脏内毒素（脂多糖，LPS）清除受损会导致内毒素血症和肿瘤坏死因子α（TNF-α）释放。TNF-α介导AML细胞系中的抗增殖和分化作用。急性病毒性肝炎中释放的干扰素-γ（IFN-γ）与TNF-α协同作用。用生理上可达到的TNF-α（10 U/ml）、IFN-γ（100 U/ml）和LPS（10 ng/ml）水平处理3天、6天和9天的HL60、KG1和U937 AML细胞，与对照组相比，其活力和细胞生长显著降低。用LPS/TNF-α/IFN-γ处理HL60 AML细胞也导致单核细胞途径分化显著增加，而KG1或U937 AML细胞则未出现这种情况。与未用LPS刺激的TNF-α/IFN-γ处理细胞或未处理细胞（p<0.0001）中小于0.01 U/10⁶细胞相比，用TNF-α/IFN-γ处理6天的HL60 AML细胞在LPS刺激后释放内源性TNF-α（1.57 U/10⁶细胞）。与对照组相比，未处理的HL60 AML细胞与用TNF-α/IFN-γ预处理6天然后接受LPS刺激的HL60细胞共培养，其细胞生长显著降低（p<0.0001）。这种作用可用抗TNF-α抗体逆转，支持以下概念：LPS/TNF-α/IFN-γ处理的HL60 AML细胞释放的内源性TNF-α可能通过旁分泌方式抑制其他AML细胞的生长。输血后肝炎对AML患者的有益作用可能通过LPS/TNF-α/IFN-γ诱导的AML细胞生长抑制和/或终末分化介导，其中AML细胞在受到LPS/TNF-α/IFN-γ作用后通过释放TNF-α参与其中。内源性释放的TNF-α然后可能通过自分泌/旁分泌方式介导进一步的抑制和终末分化。
