“Host Tissue Damage ” Signal ATP Promotes Non-directional Migration and Negatively Regulates Toll-like Receptor

The activation of Toll-like receptors (TLRs) by lipopolysac-charide or other ligands evokes a proinflammatory immune response, which is not only capable of clearing invading patho-gens but can also inflict damage to host tissues. It is therefore important to prevent an overshoot of the TLR-induced response where necessary, and here we show that extracellular ATP is capable of doing this in human monocytes. Using reverse tran-scription-PCR, we showed that monocytes express P2Y1, P2Y2, P2Y4, P2Y11, and P2Y13 receptors, as well as several P2X recep-tors. To elucidate the function of these receptors, we first studied Ca2 signaling in single cells. ATP or UTP induced a biphasic increase in cytosolic Ca2, which corresponded to internal Ca2 release followed by activation of store-operated Ca2 entry. The evoked Ca2 signals stimulated Ca2-activated K channels, producing transient membrane hyperpolarization. In addition