Felli Nadia, Pedini Francesca, Zeuner Ann, Petrucci Eleonora, Testa Ugo, Conticello Concetta, Biffoni Mauro, Di Cataldo Andrea, Winkles Jeffrey A, Peschle Cesare, De Maria Ruggero
Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.
J Immunol. 2005 Aug 1;175(3):1464-72. doi: 10.4049/jimmunol.175.3.1464.
IFN-gamma inhibits the growth and differentiation of erythroid precursor cells and mediates hemopoietic suppression through mechanisms that are not completely understood. We found that treatment of human erythroid precursor cells with IFN-gamma up-regulates the expression of multiple members of the TNF family, including TRAIL and the recently characterized protein TWEAK. TWEAK and its receptor fibroblast growth factor-inducible 14 (Fn14) were expressed by purified erythroblasts at all the stages of maturation. Exposure to recombinant TWEAK or agonist anti-Fn14 Abs was able to inhibit erythroid cell growth and differentiation through caspase activation. Because other members of the TNF family such as TRAIL and CD95 ligand (CD95L) are known to interfere with erythroblast growth and differentiation, we investigated the role of different TNF/TNFR family proteins as potential effectors of IFN-gamma in the immature hemopoietic compartment. Treatment of erythroid precursor cells with agents that blocked either TRAIL, CD95L, or TWEAK activity was partially able to revert the effect of IFN-gamma on erythroid proliferation and differentiation. However, the simultaneous inhibition of TRAIL, TWEAK, and CD95L resulted in a complete abrogation of IFN-gamma inhibitory effects, indicating the requirement of different receptor-mediated signals in IFN-gamma-mediated hemopoietic suppression. These results establish a new role for TWEAK and its receptor in normal and IFN-gamma-mediated regulation of hematopoiesis and show that the effects of IFN-gamma on immature erythroid cells depend on multiple interactions between TNF family members and their receptors.
干扰素-γ抑制红系前体细胞的生长和分化，并通过尚未完全明确的机制介导造血抑制。我们发现，用干扰素-γ处理人红系前体细胞会上调肿瘤坏死因子（TNF）家族多个成员的表达，包括肿瘤坏死因子相关凋亡诱导配体（TRAIL）和最近鉴定的蛋白肿瘤坏死因子样弱凋亡诱导因子（TWEAK）。TWEAK及其受体成纤维细胞生长因子诱导14（Fn14）在纯化的各成熟阶段的成红细胞中均有表达。暴露于重组TWEAK或激动剂抗Fn14抗体能够通过激活半胱天冬酶抑制红系细胞的生长和分化。由于已知TNF家族的其他成员如TRAIL和CD95配体（CD95L）会干扰成红细胞的生长和分化，我们研究了不同的TNF/TNFR家族蛋白作为干扰素-γ在未成熟造血区室中潜在效应分子的作用。用阻断TRAIL、CD95L或TWEAK活性的试剂处理红系前体细胞，部分能够逆转干扰素-γ对红系增殖和分化的影响。然而，同时抑制TRAIL、TWEAK和CD95L会导致干扰素-γ抑制作用完全消除，表明在干扰素-γ介导的造血抑制中需要不同的受体介导信号。这些结果确立了TWEAK及其受体在正常和干扰素-γ介导的造血调控中的新作用，并表明干扰素-γ对未成熟红系细胞的作用取决于TNF家族成员与其受体之间的多种相互作用。
