Williams A S, Topley N, Williams B D
Rheumatology Research Laboratory, University of Wales College of Medicine, Heath Park, Cardiff, UK.
Biochim Biophys Acta. 1994 Jan 11;1225(2):217-22. doi: 10.1016/0925-4439(94)90081-7.
The ability of liposomally encapsulated preparations of methotrexate (MTX) and three of its lipophilic derivatives (MTX-gamma-DMPE, MTX-alpha-DMPE and MTX-alpha,gamma-diDMPE) to alter mediator release by lipopolysaccharide (LPS)-stimulated rat peritoneal macrophages (PM theta) was investigated. The viability of these macrophages when incubated with approximately 6.0 nmol/10(5) cells of the respective liposomal preparations (MTX-LIPO, MTX-gamma-LIPO, MTX-alpha-LIPO and MTX-di-LIPO) for 20 h was greater than 80%. Treatment of macrophages, which had been incubated with MTX-alpha-LIPO (5.5 nmol/10(5) cells), MTX-gamma-LIPO (6.9 nmol/10(5) cells) and MTX-di-LIPO (4.5 nmol/10(5) cells) for 20 h, with antibody-coated sheep red blood cells resulted in 105 +/- 9.6%, 80.6 +/- 5.6% and 91 +/- 11.4% phagocytosis respectively (mean +/- S.E.M.). At similar concentrations of MTX-alpha-LIPO, MTX-gamma-LIPO and MTX-di-LIPO (6.5 nmol/10(5) cells), PGE2 release from LPS-stimulated rat peritoneal macrophages was inhibited by 85.3 +/- 3.7%, 68.7 +/- 0.6% and 88.8 +/- 2.2%, respectively (mean +/- S.E.M., n = 4). Incubation of these macrophages with 12, 10 and 9.4 nmol/10(5) cells of the respective liposomal preparations resulted in 89 +/- 3.3%, 62 +/- 5.5% and 85 +/- 3.9% inhibition of TNF alpha release (mean +/- S.E.M., n = 4). However, at this concentration MTX-di-LIPO was toxic. Neither MTX (20-2.5 nmol/10(5) cells) nor MTX-LIPO (5.6 nmol/10(5) cells) affected TNF alpha release from LPS-stimulated macrophages. Whilst free MTX was also ineffective at inhibiting PGE2 from these cells, incubation with MTX-LIPO at the above concentration resulted in 76.9 +/- 2.6% inhibition of the prostaglandins release.
研究了甲氨蝶呤（MTX）及其三种亲脂性衍生物（MTX-γ-DMPE、MTX-α-DMPE和MTX-α,γ-二DMPE）的脂质体包封制剂改变脂多糖（LPS）刺激的大鼠腹腔巨噬细胞（PMθ）介质释放的能力。当这些巨噬细胞与相应脂质体制剂（MTX-LIPO、MTX-γ-LIPO、MTX-α-LIPO和MTX-二-LIPO）以约6.0 nmol/10⁵个细胞的浓度孵育20小时时，其活力大于80%。用抗体包被的绵羊红细胞处理已与MTX-α-LIPO（5.5 nmol/10⁵个细胞）、MTX-γ-LIPO（�.9 nmol/10⁵个细胞）和MTX-二-LIPO（4.5 nmol/10⁵个细胞）孵育20小时的巨噬细胞，吞噬作用分别为105±9.6%、80.6±5.6%和91±11.4%（平均值±标准误）。在MTX-α-LIPO、MTX-γ-LIPO和MTX-二-LIPO浓度相似（6.5 nmol/10⁵个细胞）时，LPS刺激的大鼠腹腔巨噬细胞释放PGE₂分别被抑制85.3±3.7%、68.7±0.6%和88.8±2.2%（平均值±标准误，n = 4）。用相应脂质体制剂以12、10和9.4 nmol/10⁵个细胞的浓度孵育这些巨噬细胞，导致TNFα释放分别被抑制89±3.3%、62±5.5%和85±3.9%（平均值±标准误，n = 4）。然而，在此浓度下MTX-二-LIPO有毒性。MTX（20 - 2.5 nmol/10⁵个细胞）和MTX-LIPO（5.6 nmol/10⁵个细胞）均不影响LPS刺激的巨噬细胞释放TNFα。虽然游离MTX对抑制这些细胞释放PGE₂也无效，但以上述浓度与MTX-LIPO孵育导致前列腺素释放被抑制76.9±2.6%。
