TGF-β Inhibits Fas-Mediated Apoptosis of a Follicular Dendritic Cell Line by Down-Regulating the Expression of Fas and Caspase-8: Counteracting Role of TGF-β on TNF Sensitization of Fas-Mediated Apoptosis

Abstract

Follicular dendritic cells (FDC) constitute the framework of germinal center (GC) in secondary lymphoid follicles, and the integrity of FDC networks is critically affected by cytokines present in the GC. We have previously shown that TNF promotes Fas-mediated apoptosis of HK cells, an established FDC-like cell line, by up-regulating Fas expression. However, in the developing GC, FDC death is not a hallmark of GC despite the presence of TNF and FasL. In this study, we report that TGF-β inhibits Fas-mediated apoptosis of HK cells by down-regulating the expression of surface Fas and caspase-8. The inhibitory effect of TGF-β can be observed when HK cells were simultaneously treated with TNF and TGF-β, indicating that TGF-β counteracts the effect of TNF in sensitizing cells to Fas-mediated apoptosis. Furthermore, the deprivation of TGF-β by injecting neutralizing TGF-β Abs to the SRBC-immunized mice resulted in the sporadic appearance of FDC undergoing apoptosis in the lymphoid follicles, suggesting that TGF-β functions as a naturally occurring inhibitor that rescues FDCs which are predisposed to apoptosis. Our study documents a novel function of TGF-β in the maintenance of FDC networks.

Proteomic Pathway Analysis Reveals Inflammation Increases Myeloid-Derived Suppressor Cell Resistance to Apoptosis

“…When activated by phosphorylation, p38 kinase inhibits the activation (auto-cleavage) of caspase-3 and caspase-8 (35). Multiple stimuli induce p38 activation, including transforming growth factor beta (TGF-␤ (36)), which directly downregulates Fas-mediated apoptosis (37). Interestingly, our pathway analysis identified both TGF-␤ and p38 pathways as up-regulated in inflammatory MDSC as compared with conventional MDSC (Fig.…”

STAT6 and JAK1 are essential for IL-4-mediated suppression of prostaglandin production in human follicular dendritic cells: Opposing roles of phosphorylated and unphosphorylated STAT6

“…TGF-β also induces apoptosis in human centroblasts [26]. Although Lee et al suggested a protective role for TGF-β in the apoptosis of FDC [27], the physiological importance of TGF-β in FDC functions is unclear. Using an in vitro experimental model containing primary FDC-like cells, we suggested that TGF-β induces PG production from FDC and then secreted PG inhibits proliferation and apoptosis of T cells [10].…”

Establishment of Lymphotoxin β Receptor Signaling-Dependent Cell Lines with Follicular Dendritic Cell Phenotypes from Mouse Lymph Nodes

“…In contrast, a human cell line, HK, has been established from tonsil, and widely used as a FDC-like cell line (30). HK cells retain some properties characteristic of FDCs, including LT␣1␤2-induced upregulation of cell adhesion molecules (ICAM-1 and VCAM-1) and cytokines (IL-6, IL-15) (55), TNF-induced NF-B activation (56), and supporting GC B cell survival and proliferation (38,(55)(56)(57)(58)(59)(60)(61), while it has been reported that HK cells lost a representative surface marker of FDCs, CD21, shortly after isolation from human tonsil (30).…”

“…Feeder cells were prepared by treating LN cells (2 ϫ 10 7 cells/ml) from TNP-KLH-primed BALB/c mice with 25 g/ml mitomycin C for 30 min at 37°C. TGF-␤1 was usually added, as it has been reported to inhibit Fas-mediated apoptosis in a human FDC-like cell line (38). IL-4 was sometimes replaced by 10% (v/v) Con A-sup.…”