Prednisolone Suppresses the Function and Promotes Apoptosis of Plasmacytoid Dendritic Cells

Abstract

Organ transplant recipients are highly susceptible to viral infections early after transplantation. Plasmacytoid dendritic cells (PDC) play a major role in antiviral immunity. Therefore, we determined the numbers of circulating PDC after liver transplantation (LTX) and established the effects of immunosuppressive drugs on PDC survival and function. PDC were determined longitudinally in 13 LTX recipients treated with prednisone and cyclosporin or tacrolimus. Purified PDC were cultured with or without clinically relevant concentrations of cyclosporin, tacrolimus or prednisolone. Apoptosis induction was monitored by determination of active caspase-3, nuclear condensation and annexin-V/7AAD staining. After LTX, a 4-fold reduction in the number of circulating PDC was observed (p < 0.01), which recovered partially after discontinuation of prednisone treatment. In vitro, prednisolone induced apoptosis in PDC, while cyclosporin and tacrolimus did not. Higher doses of prednisolone were needed to induce apoptosis in Toll-like receptor (TLR)-stimulated PDC. However, non-apoptosis inducing concentrations of prednisolone suppressed interferon-alpha production, upregulation of co-stimulatory molecules and allo-stimulatory capacity of TLR-stimulated PDC. In conclusion, prednisolone induces apoptosis in PDC, which explains the decline in circulating PDC numbers after transplantation. Moreover, prednisolone suppresses the functions of TLR-stimulated PDC. Therefore, corticosteroid-free immunosuppressive therapy may reduce the number and severity of viral infections after transplantation.

Plasmacytoid dendritic cells in pulmonary lymphoid follicles of patients with COPD

“…An increased maturational response of pDCs in severe COPD, as suggested by FREEMAN et al [17], could also explain the lower numbers of BDCA-2-positive pDCs. Finally, the use of inhaled and systemic corticosteroids by patients with severe and very severe COPD could contribute to the reduced number of pDCs in this study, as these drugs are known to induce apoptosis in circulating and tissue-resident pDCs [36][37][38][39]. This lower number of pDCs in lymphoid follicles of patients with very severe COPD treated with inhaled steroids could be linked to the observed association of increased risk of pneumonia and the use of inhaled corticosteroids in patients with COPD [40].…”

Toll-like receptor control of glucocorticoid-induced apoptosis in human plasmacytoid predendritic cells (pDCs)

“…24 Viability of freshly sorted normal blood pDC (Ͼ 99% purity) after 24 hours in culture medium was consistently Ͻ 30% and was further decreased in a dose-dependent manner in the presence of the natural GC hydrocortisone ( Figure 1A), confirming that pDCs are sensitive to GC-induced apoptosis. 14 We asked whether IL-3, which promotes pDC survival and activation, 25 was able to protect pDCs from GC-induced apoptosis. IL-3 (10 ng/mL) promoted good pDC viability after 24 hours of culture as assessed by trypan blue exclusion of dead cells ( Figure 1B).…”

“…8 A major mechanism by which GCs mediate anti-inflammatory responses is to induce apoptosis of several immune cell types, 9 including eosinophils, 10 activated T cells, 11 thymocytes, 3,12 monocytes, 4 dendritic cells (DCs), 13 and plasmacytoid predendritic cells (pDCs). 14 Induction of apoptosis by GCs appear to be more restricted to immune cells, because GCs have antiapoptotic effects on epithelial cells, such as mammary gland, hepatocytes, and ovarian follicular cells. 15,16 Another mechanism is that GCs inhibit the production of proinflammatory cytokines, such as tumor necrosis factor-␣ (TNF-␣), interleukin-1 (IL-1), IL-6, and IL-12, by interfering with the nuclear factor B (NFB) pathway.…”

Dendritic Cell Apoptosis: Regulation of Tolerance versus Immunity

“…Patients and healthy volunteers treated with corticosteroids show a decrease in the levels of circulating pDCs (45). It has been shown that glucocorticoid treatment of human pDCs can induce apoptosis via the extrinsic pathway (46). Tumor-induced DC apoptosis.…”