Adem Jemal, Eray Mine, Eeva Jonna, Nuutinen Ulla, Pelkonen Jukka
Department of Clinical Microbiology, Institute of Clinical Medicine, University of Eastern Finland, Yliopistonranta 1 C, 70210, Kuopio, Finland.
Department of pathology (HUSLAB), Helsinki University Hospital, Helsinki, Finland.
Immunobiology. 2017 Nov;222(11):998-1003. doi: 10.1016/j.imbio.2017.06.001. Epub 2017 Jun 10.
CD40 is a cell surface receptor which belongs to tumor necrosis factor receptor (TNFR) family members. It transmits signals that regulate diverse cellular responses such as proliferation, differentiation, adhesion molecule expression and apoptosis. Unlike other TNFR family members (TRAIL-R, Fas-R and TNFR1), the CD40 cytoplasmic tail lacks death domain. However, CD40 is capable of inducing apoptosis in different types of cancer cells including lymphoma. The apoptotic effect of CD40 is linked to the involvement of Fas, TRAIL or receptor interacting protein 1 (RIP1) kinase. We have previously shown that CD40 activation has anti-apoptotic or apoptotic effect in follicular lymphoma (FL) cell lines. In this study, we investigated the mechanism by which CD40 mediates apoptosis in a follicular lymphoma cell line, HF4.9. We show here that CD40-induced apoptosis was dependent on caspase-8 activation because caspase-8 specific inhibitor, Z-IETD-FMK completely prevented apoptosis. Therefore, the involvement of TRAIL, Fas and RIP1 in caspase-8 activation was examined. The exogenous TRAIL-induced apoptosis was fully prevented by anti-TRAIL neutralizing antibody. However, the antibody had no effect on CD40-induced apoptosis indicating that CD40 did not induce the expression of endogenous TRAIL in HF4.9 cells. Moreover, the cells were not sensitive to Fas-mediated apoptosis. Interestingly, RIP1 specific inhibitor, necrostatin-1 decreased CD40-induced apoptosis, which showed that RIP1 has a role in caspase-8 activation. In conclusion, the survival or apoptotic effects of CD40-mediated signaling might be related to the differentiation stages of FL cells.
CD40是一种细胞表面受体，属于肿瘤坏死因子受体（TNFR）家族成员。它传递调节多种细胞反应的信号，如增殖、分化、黏附分子表达和凋亡。与其他TNFR家族成员（TRAIL-R、Fas-R和TNFR1）不同，CD40的细胞质尾部缺乏死亡结构域。然而，CD40能够在包括淋巴瘤在内的不同类型癌细胞中诱导凋亡。CD40的凋亡作用与Fas、TRAIL或受体相互作用蛋白1（RIP1）激酶的参与有关。我们之前已经表明，CD40激活在滤泡性淋巴瘤（FL）细胞系中具有抗凋亡或促凋亡作用。在本研究中，我们研究了CD40在滤泡性淋巴瘤细胞系HF4.9中介导凋亡的机制。我们在此表明，CD40诱导的凋亡依赖于半胱天冬酶-8的激活，因为半胱天冬酶-8特异性抑制剂Z-IETD-FMK完全阻止了凋亡。因此，研究了TRAIL、Fas和RIP1在半胱天冬酶-8激活中的参与情况。外源性TRAIL诱导的凋亡被抗TRAIL中和抗体完全阻止。然而，该抗体对CD40诱导的凋亡没有影响，表明CD40在HF4.9细胞中没有诱导内源性TRAIL的表达。此外，这些细胞对Fas介导的凋亡不敏感。有趣的是，RIP1特异性抑制剂坏死素-1降低了CD40诱导的凋亡，这表明RIP1在半胱天冬酶-8激活中起作用。总之，CD40介导的信号传导的存活或凋亡作用可能与FL细胞的分化阶段有关。
