期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2004
卷号：101
期号：25
页码：9479-9484
DOI：10.1073/pnas.0400733101
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：The effects of low concentrations of extracellular ATP on cytosolic Ca2+, membrane potential, and transcription of IL-6 were studied in monocyte-derived human macrophages. During inflammation or infection many cells secrete ATP. We show here that application of 10 {micro}M ATP or 10 {micro}M UTP induces oscillations in cytosolic Ca2+ with a frequency of {approx}12 min-1 and oscillations in membrane potential. RT-PCR analysis showed expression of P2Y1, P2Y2, P2Y11, P2X1, P2X4, and P2X7 receptors, large-conductance (KCNMA1 and KCNMB1-4), and intermediate-conductance (KCNN4) Ca2+-activated K+ channels. The Ca2+oscillations were unchanged after removal of extracellular Ca2+, indicating that they were mainly due to movements of Ca2+ between intracellular compartments. Comparison of the effects of different nucleotides suggests that the Ca2+ oscillations were elicited by activation of P2Y2 receptors coupled to phospholipase C. Patch-clamp experiments showed that ATP induced a transient depolarization, probably mediated by activation of P2X4 receptors, followed by membrane potential oscillations due to opening of Ca2+-activated K+ channels. We also found that 10 {micro}M ATP{gamma}S increased transcription of IL-6 {approx}40-fold within 2 h. This effect was abolished by blockade of P2Y receptors with 100 {micro}M suramin. Our results suggest that ATP released from inflamed, damaged, or metabolically impaired cells represents a "danger signal" that plays a major role in activating the innate immune system.
