Harbrecht B G, Kim Y M, Wirant E A, Simmons R L, Billiar T R
Department of Surgery, University of Pittsburgh, Pennsylvania, USA.
J Leukoc Biol. 1997 Jun;61(6):712-20. doi: 10.1002/jlb.61.6.712.
Macrophage nitric oxide (NO) synthesis is an integral component of the host defense system. We have previously found that NO and prostaglandins interact in a variety of ways. NO modulates Kupffer cell prostaglandin E2 (PGE2) production and we have recently described the inhibitory effects of PGE2 on NO synthesis in both Kupffer cells and hepatocytes. Activated macrophages produce a number of prostaglandins but studies regarding the capacity of prostaglandins to regulate macrophage NO synthesis have yielded conflicting results. We found that exogenous PGE2 decreased lipopolysaccharide (LPS)-induced NO synthesis in murine resident peritoneal macrophages and in the RAW 264.7 murine macrophage cell line. PGE2 also suppressed NO synthesis in response to interferon-gamma (IFN-gamma) alone and a combination of LPS + IFN-gamma. Inhibition of endogenous PGE2 synthesis with indomethacin or ibuprofen had no effect on NO synthesis. PGE2 added with the activating stimulus was most effective. PGE2 lost the capacity to block NO synthesis if added more than 180 min after LPS. PGE2 decreased inducible NO synthesis (iNOS) mRNA and immunoreactive iNOS protein, consistent with the hypothesis that exogenous PGE2 inhibits macrophage iNOS expression but that the inhibition depends on the time and concentration of prostaglandin exposure.
巨噬细胞一氧化氮（NO）的合成是宿主防御系统的一个重要组成部分。我们之前发现，NO和前列腺素以多种方式相互作用。NO调节库普弗细胞前列腺素E2（PGE2）的产生，并且我们最近描述了PGE2对库普弗细胞和肝细胞中NO合成的抑制作用。活化的巨噬细胞会产生多种前列腺素，但关于前列腺素调节巨噬细胞NO合成能力的研究结果相互矛盾。我们发现，外源性PGE2可降低脂多糖（LPS）诱导的小鼠常驻腹膜巨噬细胞和RAW 264.7小鼠巨噬细胞系中的NO合成。PGE2还可抑制单独由干扰素-γ（IFN-γ）以及LPS + IFN-γ联合刺激所引起的NO合成。用吲哚美辛或布洛芬抑制内源性PGE2合成对NO合成没有影响。与激活刺激物同时添加PGE2最为有效。如果在LPS刺激180分钟后添加PGE2，则其失去阻断NO合成的能力。PGE2可降低诱导型NO合成（iNOS）的mRNA水平和具有免疫反应性的iNOS蛋白水平，这与外源性PGE2抑制巨噬细胞iNOS表达，但这种抑制取决于前列腺素暴露的时间和浓度这一假设一致。
