期刊
SHOCK
卷 34, 期 1, 页码 10-16出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/SHK.0b013e3181cdc3e2
关键词
PMN leukocytes; T cells; A(2A) receptor; cAMP; sepsis
资金
- Department of Anaesthesiology, Ludwig Maximilians University, Munich
The phosphodiesterase inhibitor pentoxifylline (PTX) exerts multiple beneficial immunomodulatory effects in states of hyperinflammation. However, the exact mechanism of action still remains elusive, and the clinical effects of PTX cannot be reliably predicted. In immune cells, the G protein-coupled adenosine A(2A) receptor (A(2A)R) exerts strong anti-inflammatory effects. As PTX amplifies signaling pathways downstream of G(s) protein-coupled receptors, the A(2A)R-signaling pathway might be involved in the mediation of immune-suppressive effects of PTX. Here, we investigated this assumption in LPS-stimulated human polymorphonuclear (PMN) leukocytes and in anti-CD3/CD28-stimulated human T cells. In stimulated PMN leukocytes, PTX treatment led to a 4.5-fold decrease of the 50% inhibitory concentrations of adenosine on the H2O2 production; i.e., for adenosine plus PTX (in clinically relevant concentrations), an overadditive increase of inhibitory effects from less than 20% (estimated for each) to 56% (+/-5%) was found. In T cells, adenosine plus PTX revealed similar synergistic inhibitory effects on proinflammatory cytokine production. Inhibition of interferon gamma and TNF-alpha production increased from 7% (+/-1%) and 31% (+/-6%) (PTX alone) to 49% (+/-2%) and 69% (+/-6%), respectively. In T cells and PMN leukocytes, mRNA transcription of the A(2A)R was significantly increased upon stimulation, which was not influenced by PTX. In human PMN leukocytes and T cells, clinically relevant anti-inflammatory effects of PTX can be achieved only in the presence of sufficient adenosine concentrations. Sufficient adenosine levels might be a prerequisite for the accessibility of sepsis patients to treatment with PTX.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据