Guerra Alma N, Fisette Philip L, Pfeiffer Zachary A, Quinchia-Rios Beatriz H, Prabhu Usha, Aga Mini, Denlinger Loren C, Guadarrama Arturo G, Abozeid Sara, Sommer Julie A, Proctor Richard A, Bertics Paul J
Department of Biomolecular Chemistry, University of Wisconsin Medical School, Madison, WI 53706-1532, USA.
J Endotoxin Res. 2003;9(4):256-63. doi: 10.1179/096805103225001468.
Macrophages express several lipopolysaccharide (LPS) binding proteins and are potently activated by LPS to produce inflammatory mediators. Recent studies have shown that receptors for exogenous nucleotides (P2X and P2Y purinergic receptors) can modulate macrophage production of TNF-alpha, IL-1beta and nitric oxide (NO) following LPS exposure. Macrophages and LPS-stimulated monocytes express elevated levels of P2Y1, P2Y2 and P2X7 mRNA, suggesting that both P2Y and P2X receptors can contribute to LPS-induced pathophysiology. In addition, oxidized-ATP treatment (which inhibits P2X7) of macrophages blocks LPS-induced NO production, NF-kappaB and ERK-1/2 activation. Also, an LPS-binding domain located in the P2X7 C-terminus appears important for receptor trafficking/function. Moreover, the purinergic receptor ligand 2-MeS-ATP attenuates LPS-induced cytokine and NO production in vivo and ex vivo. These data suggest that P2X7 and certain P2Ys are linked to LPS effects, although their relative contribution in vivo is unclear. Accordingly, we tested the capacity of several adenine nucleotides to modulate LPS-induced mortality in mice. We found that the P2X7-directed ligand BzATP was unable to prevent LPS-induced death, whereas 2-MeS-ATP and 2-Cl-ATP, which bind to multiple P2X and P2Y receptors were able to protect mice from LPS-induced death. These data suggest that the co-ordinate action of P2Y and P2X7 receptors are critical for controlling LPS responses in vivo and that agents directed against both receptor classes may provide the greatest therapeutic advantage.
巨噬细胞表达多种脂多糖（LPS）结合蛋白，并被LPS强力激活以产生炎症介质。最近的研究表明，外源性核苷酸受体（P2X和P2Y嘌呤能受体）可调节LPS刺激后巨噬细胞产生肿瘤坏死因子-α、白细胞介素-1β和一氧化氮（NO）。巨噬细胞和LPS刺激的单核细胞中P2Y1、P2Y2和P2X7 mRNA水平升高，表明P2Y和P2X受体都可能参与LPS诱导的病理生理过程。此外，对巨噬细胞进行氧化ATP处理（抑制P2X7）可阻断LPS诱导的NO产生、核因子-κB和细胞外信号调节激酶-1/2的激活。而且，位于P2X7 C末端的LPS结合结构域似乎对受体转运/功能很重要。此外，嘌呤能受体配体2-甲硫基ATP在体内和体外均可减弱LPS诱导的细胞因子和NO产生。这些数据表明，P2X7和某些P2Y与LPS的作用有关，尽管它们在体内的相对作用尚不清楚。因此，我们测试了几种腺嘌呤核苷酸调节LPS诱导的小鼠死亡的能力。我们发现，P2X7定向配体BzATP无法预防LPS诱导的死亡，而与多种P2X和P2Y受体结合的2-甲硫基ATP和2-氯ATP能够保护小鼠免受LPS诱导的死亡。这些数据表明，P2Y和P2X7受体的协同作用对于体内控制LPS反应至关重要，针对这两类受体的药物可能具有最大的治疗优势。
