Zacharowski Paula, Breese Emma, Wood Elizabeth, Del Soldato Piero, Warner Tim, Mitchell Jane
Cardiac, Vascular and Inflammation Research, The William Harvey Research Institute, Bart's and The London, Queen Mary School of Medicine and Dentistry, London, UK.
Eur J Pharmacol. 2005 Jan 31;508(1-3):7-13. doi: 10.1016/j.ejphar.2004.11.064. Epub 2004 Dec 28.
Non-steroidal anti-inflammatory drugs (NSAIDs) are used to treat the condition of rheumatoid arthritis, where levels of prostaglandin E2 (PGE2) and granulocyte macrophage-colony stimulating factor (GM-CSF) are elevated in the synovial fluid. NO-NSAIDs are a new class of cyclooxygenase (COX)-inhibitors developed by coupling a nitric oxide (NO)-donating moiety to conventional NSAIDs. We show that, in cytokine-treated synoviocytes (from non-rheumatic patients), NO-naproxen and NO-flurbiprofen like their parent compounds concentration-dependently reduce the levels of PGE2 (an index of COX-2 activity), with a corresponding rise in the release of GM-CSF. Unlike acetylsalicylic acid (ASA), NO-ASA reduces the levels of PGE2, without increasing GM-CSF release, although cell viability is reduced at the highest concentration (1 mM). The effects of NSAIDs and NO-NSAIDs on GM-CSF release were attributable to the PGE2 mediated cyclic (c) AMP pathway because PGE2 reversed the effects of COX blockade. Second, phosphodiesterase inhibitors 3-isobutyl-1-methylxanthine (IBMX) and Ro-201724 (both of which elevate cAMP levels) decreased GM-CSF release, in the presence of PGE2. Finally, neither sodium nitroprusside nor zaprinast (both of which elevate cGMP levels) affected GM-CSF or PGE2 release. Our findings demonstrate that GM-CSF is regulated by NSAIDs and NO-NSAIDs via inhibition of COX and appears to be mediated via the cAMP pathway. NO-ASA is the exception, because it does not increase GM-CSF release, although at millimolar concentrations cell viability is reduced.
非甾体抗炎药（NSAIDs）用于治疗类风湿性关节炎，在这种疾病中，滑液中前列腺素E2（PGE2）和粒细胞巨噬细胞集落刺激因子（GM-CSF）的水平会升高。NO-NSAIDs是一类新型的环氧化酶（COX）抑制剂，通过将一氧化氮（NO）供体部分与传统NSAIDs偶联而开发。我们发现，在细胞因子处理的滑膜细胞（来自非风湿性患者）中，NO-萘普生和NO-氟比洛芬与其母体化合物一样，浓度依赖性地降低PGE2水平（COX-2活性指标），同时GM-CSF释放相应增加。与阿司匹林（ASA）不同，NO-ASA降低PGE2水平，且不增加GM-CSF释放，尽管在最高浓度（1 mM）时细胞活力会降低。NSAIDs和NO-NSAIDs对GM-CSF释放的影响归因于PGE2介导的环（c）AMP途径，因为PGE2可逆转COX阻断的作用。其次，磷酸二酯酶抑制剂3-异丁基-1-甲基黄嘌呤（IBMX）和Ro-201724（两者均可提高cAMP水平）在PGE2存在的情况下可降低GM-CSF释放。最后，硝普钠和扎普司特（两者均可提高cGMP水平）均不影响GM-CSF或PGE2释放。我们的研究结果表明，GM-CSF受NSAIDs和NO-NSAIDs通过抑制COX进行调节，且似乎是通过cAMP途径介导的。NO-ASA是个例外，因为它不增加GM-CSF释放，但在毫摩尔浓度下细胞活力会降低。
