Adenosine is upregulated during peritonitis and is involved in downregulation of inflammation
Adenosine is upregulated during peritonitis and is involved in downregulation of inflammation
复制标题
DOI：
10.1038/sj.ki.5001609
复制
发表时间：
2006-08-01
影响因子：
19.6
通讯作者：
Douvdevani, A.
中科院分区：
文献类型：
--
作者：
Rogachev, B.;Ziv, N. Y.;Douvdevani, A.
腹膜功能丧失与腹膜炎有关。炎症部位的腺苷水平增加，并表现出免疫调节作用。我们的目的是阐明腺苷在腹膜炎中的调节作用，并测试腹膜间皮细胞(PMC)参与腺苷调节的情况。在大肠杆菌腹膜炎的小鼠模型中，腺苷A(2A)受体(A(2A)R)激动剂(CGS21680)阻止白细胞募集，并降低肿瘤坏死因子α(TNF-α)和白细胞介素6(IL-6)水平。腹膜腺苷受体水平分析表明，A(1)受体(A(1)R)蛋白水平在接种后12 h达高峰，24 h后恢复到基础水平，而高亲和力A(2A)R蛋白水平在24 h达到峰值，同时腺苷浓度也达到峰值。低亲和力A(2B)受体(A(2B)R)水平缓慢升高，持续至48h。在人PMC(HPMC)中，早期细胞因子IL-1-α和TNF-α上调A(2B)和A(2A)受体。然而，干扰素-γ上调了A(2B)R，降低了A(2A)R水平。用A(2A)受体激动剂治疗可减少HPMC分泌IL-1依赖的IL-6。结论：腺苷受体动力学表明，腹膜炎早期以A(1)R为主，以后被抑制炎症的G刺激(Gs)蛋白偶联A(2A)R所取代。早期的促炎细胞因子是A(2A)受体的诱导者，这种受体减少了它们的产生和白细胞的募集。今后应考虑使用腺苷激动剂来减轻急性腹膜炎过程中对间皮细胞的损害。
Loss of function of the peritoneal membrane is associated with peritonitis. Adenosine levels in sites of inflammation were shown to increase and exhibit immunoregulatory effects. Our aim was to elucidate the regulatory role of adenosine during peritonitis and to test the involvement of peritoneal mesothelial cells (PMC) in adenosine regulation. In a mice model of Escherichia coli peritonitis, the adenosine A(2A) receptor (A(2A)R) agonist (CGS21680) prevented leukocyte recruitment and reduced tumor necrosis factor alpha (TNF-alpha) and interleukin-6 (IL-6) levels. Peritonitis induced the elevation of adenosine with a peak at 24 h. Analysis of adenosine receptor levels on peritoneum showed that A(1) receptor (A(1)R) protein levels peak at 12 h after inoculation and then return to baseline at 24 h, whereas high affinity A(2A)R protein levels peak at 24 h concomitantly with the peak of adenosine concentration. Low affinity A(2B) receptor (A(2B)R) levels elevated slowly, remaining elevated up to 48 h. In human PMC (HPMC), the early cytokines, IL-1-alpha, and TNF-alpha upregulated the A(2B) and A(2A) receptors. However, interferon-gamma (IFN-gamma) upregulated the A(2B)R and decreased A(2A)R levels. Treatment with the A(2A)R agonist reduced IL-1-dependent IL-6 secretion from HPMC. In conclusion, the kinetics of adenosine receptors suggest that at early stage of peritonitis, the A(1)R dominates, and later its dominance is replaced by the G stimulatory (Gs) protein-coupled A(2A)R that suppresses inflammation. Early proinflammatory cytokines are an inducer of the A(2A)R and this receptor reduces their production and leukocyte recruitment. Future treatment with adenosine agonists should be considered for attenuating the damage to mesothelium during the course of acute peritonitis.