tailieunhanh - Báo cáo y học: "Tumor necrosis factor-alpha promotes survival in methotrexate-exposed macrophages by an NF-B-dependent pathwa"

Tuyển tập các báo cáo nghiên cứu về y học được đăng trên tạp chí y học General Psychiatry cung cấp cho các bạn kiến thức về ngành y đề tài: Tumor necrosis factor-alpha promotes survival in methotrexate-exposed macrophages by an NF- B-dependent pathway. | Lo et al. Arthritis Research Therapy 2011 13 R24 http content 13 1 R24 RESEARCH ARTICLE Open Access Tumor necrosis factor-alpha promotes survival in methotrexate-exposed macrophages by an NF- B-dependent pathway Susan ZY Lo James H Steer David A Joyce Abstract Introduction Methotrexate MTX induces macrophage apoptosis in vitro but there is not much evidence for increased synovial macrophage apoptosis in MTX-treated patients. Macrophage apoptosis is reported however during clinical response to anti-tumor necrosis factor-alpha TNF-a treatments. This implies that TNF-a promotes macrophage survival and suggests that TNF-a may protect against MTX-induced apoptosis. We therefore investigated this proposal and the macrophage signaling pathways underlying it. Methods Caspase-3 activity annexin-V binding 7-aminoactinomycin D 7-AAD exclusion and cell-cycle analysis were used to measure steps in apoptosis of primary murine macrophages and cells of the macrophage cell line that had been exposed to clinically-relevant concentrations of MTX and TNF-a. Results MTX induces apoptosis in primary murine macrophages at concentrations as low as 100 nM in vitro. TNF-a which has a context-dependent ability to increase or to suppress apoptosis efficiently suppresses MTX-induced macrophage apoptosis. This depends on NF-kB signaling initiated through TNF Receptor Type 1 ligation. Macrophage colony stimulating factor the primary macrophage survival and differentiation factor does not activate NF-kB or protect macrophages from MTX-induced apoptosis. A weak NF-kB activator Receptor Activator of NF-kB Ligand RANKL is likewise ineffective. Blocking NF-kB in TNF-a-exposed macrophages allowed pro-apoptotic actions of TNF-a to dominate even in the absence of MTX. MTX itself does not promote apoptosis through interference with NF-kB signaling. Conclusions These findings provide another mechanism by which TNF-a sustains macrophage numbers in inflamed tissue and .