Functional effects of TNF-α on a human follicular dendritic cell line: Persistent NF-κB activation and sensitization for Fas-mediated apoptosis

Follicular dendritic cells (FDC) play crucial roles in germinal center (GC) formation and differentiation of GC B cells. FDC functions are influenced by cytokines produced in the GC. Among the GC cytokines, TNF is known to be essential for the formation and maintenance of the FDC network in the GC. We found that TNF is a mitogenic growth factor to an established FDC-like cell line, HK cells. Differing from most cell types which become desensitized to TNF action, HK cells exhibited persistent TNF signaling, as demonstrated by prolonged and biphasic NF-κB activation even after 3 days of TNF treatment. As a result, antiapoptotic genes including TNFR-associated factors 1 and 2, and cellular inhibitor of apoptosis proteins 1 and 2 were persistently induced by TNF, leading to the protection against TNF-mediated cell death. However, TNF pretreatment enhanced Fas-mediated apoptosis by up-regulating surface Fas expression in an NF-κB-dependent pathway. During the GC responses, proliferation followed by FDC death has not been documented. However, our in vitro results suggest that FDCs proliferate in response to TNF, and die by Fas-mediated apoptosis whose susceptibility is enhanced by TNF, representing a mode of action for TNF in the maintenance of FDC networks by regulating the survival or death of FDC.