Tendler C L, Greenberg S J, Burton J D, Danielpour D, Kim S J, Blattner W A, Manns A, Waldmann T A
Metabolism Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892.
J Cell Biochem. 1991 Aug;46(4):302-11. doi: 10.1002/jcb.240460405.
The human T-cell lymphotropic virus type I (HTLV-I) is capable of inducing a variety of host cellular genes including many of the cytokines responsible for immune regulation and osteoclast activation. This derangement in cytokine expression may contribute to the panoply of disease states associated with HTLV-I infection such as the adult T-cell leukemia (ATL) and HTLV-I associated myelopathy/tropical spastic paraparesis (HAM/TSP). We wished to determine if there was a correlation between the expression of an array of cytokines and the diverse clinical manifestations of ATL and HAM/TSP. Utilizing the techniques of specific mRNA amplification by the polymerase chain reaction (PCR) as well as Northern blotting, we analyzed the ex vivo mRNA expression of gamma-interferon (IFN-gamma), tumor necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL-1 beta), and transforming growth factor-beta 1 (TGF-beta 1) in the peripheral blood of HAM/TSP and ATL patients as well as asymptomatic seropositive carriers. IFN-gamma, TNF-alpha, and IL-1 beta transcripts were up-regulated in patients with HAM/TSP and seropositive carriers when compared to their levels in ATL and normal controls. In contrast, the ATL patients constitutively expressed higher levels of TGF-beta 1 mRNA than HAM/TSP and seropositive carriers. In addition, TNF-alpha and IL-1 beta serum levels were elevated in HAM/TSP, but not in ATL patients nor seropositive carriers. However, the circulating leukemic cells from ATL patients secreted increased levels of TGF-beta 1 protein into the culture medium than T-cells derived from HAM/TSP patients. Collectively these results suggest that induction of IFN-gamma, TNF-alpha, and IL-1 beta in HAM/TSP may initiate an inflammatory cascade with subsequent events leading to immune mediated destruction of the central nervous system in these patients. Expression of osteoclast activators such as TNF-alpha and IL-1 beta is not associated with hypercalcemia in ATL. Finally, impaired cellular and humoral immune responses present in ATL, but not in HAM/TSP, may be related to elevated levels of TGF-beta 1 produced by the leukemic cells. These differences in retroviral-induced host cytokine expression in ATL and HAM/TSP suggest alternate roles in disease pathogenesis.
人类嗜T细胞病毒I型（HTLV-I）能够诱导多种宿主细胞基因，包括许多负责免疫调节和破骨细胞活化的细胞因子。细胞因子表达的这种紊乱可能导致与HTLV-I感染相关的一系列疾病状态，如成人T细胞白血病（ATL）和HTLV-I相关脊髓病/热带痉挛性截瘫（HAM/TSP）。我们希望确定一系列细胞因子的表达与ATL和HAM/TSP的不同临床表现之间是否存在相关性。利用聚合酶链反应（PCR）以及Northern印迹法进行特异性mRNA扩增技术，我们分析了HAM/TSP和ATL患者以及无症状血清阳性携带者外周血中γ-干扰素（IFN-γ）、肿瘤坏死因子-α（TNF-α）、白细胞介素-1β（IL-1β）和转化生长因子-β1（TGF-β1）的体外mRNA表达。与ATL患者和正常对照相比，HAM/TSP患者和血清阳性携带者中的IFN-γ、TNF-α和IL-1β转录本上调。相反，ATL患者组成性表达的TGF-β1 mRNA水平高于HAM/TSP患者和血清阳性携带者。此外，HAM/TSP患者的TNF-α和IL-1β血清水平升高，但ATL患者和血清阳性携带者中未升高。然而，与来自HAM/TSP患者的T细胞相比，ATL患者的循环白血病细胞向培养基中分泌的TGF-β1蛋白水平增加。总体而言，这些结果表明，HAM/TSP中IFN-γ、TNF-α和IL-1β的诱导可能引发炎症级联反应，随后的事件导致这些患者中枢神经系统的免疫介导破坏。破骨细胞激活剂如TNF-α和IL-1β的表达与ATL中的高钙血症无关。最后，ATL中存在的细胞和体液免疫反应受损，但HAM/TSP中不存在，可能与白血病细胞产生的TGF-β1水平升高有关。ATL和HAM/TSP中逆转录病毒诱导的宿主细胞因子表达的这些差异表明它们在疾病发病机制中具有不同作用。
