The opposing roles of TNFα and TGFβ1 in Fas-mediated apoptosis of follicular dendritic cells

다국어 초록 (Multilingual Abstract)

The germinal centers(GC) of secondary lymphoid follicles provide a dynamic microenvironment where mature B cells localize, proliferate, and differentiate into memory B cells. The GC reaction accompanies with the increased proliferation of follicular dendritic cells(FDC) which are in close contact with antigen-specific B cells. These cells present unprocessed antigens and provide signals for costimulation to the GC B cells. It has been well documented that cytokines of the tumor nectosis factor-α(TNFα) family play essential roles in the development of FDC network. In addition, recent studies have revealed that FDC can also express some receptors implicated in the generation of growth-inhibitory or apoptotic death signals such as transforming growth factor-β(TGFβ1) receptor and Fas, respectively. However, there is little information about the regulatory action of TNFα or TGFβ1 affecting the growth and survival of FDC. Here, using an established FDC line HK cells, we showed that TNFα is a mitogenic growth factor to HK cells. Differing from most cell types which become desensitized to TNFα action within an hour, HK cells were shown to exhibit persistent TNFα signaling, resulting in the prolonged induction of TRAF1, TRAF2, c-IAP1 and c-IAP2 genes. It has been suggested that these gene products act in concert to prevent TNFα-induced apoptosis. However, these anti-apoptotic proteins did not play roles in the protection of Fas-induced apoptosis. Rather, TNFα pretreatment was shown to sensitize cells to the Fas-mediated cell death through the NF-kB-dependent up-regulation of Fas. Interestingly, pretreatment of HK cells with TGFβ1, which was shown to cause the growth-suppressing effect on HK cells, inhibited the Fas-mediated apoptosis by down-regulating Fas expression on the surface of HK cells. Our data suggest a possible counteracting role of TNFα and TGFβ1 on Fas-mediated apoptosis of FDC, which may have implications in the organization or regression of FDC network depending on the cytokines expressed during GC reaction.