IL-18 associates to microvesicles shed from human macrophages by a LPS/TLR-4 independent mechanism in response to P2X receptor stimulation.

摘要: Extracellular ATP, released upon microbial infection, cell damage, or inflammation, acts as an alert signal toward immune cells by activating P2 receptors. The nucleotide causes microvesicle (MV) shedding from and nonimmune cells. Here, we show that IL-18 associates with MVs shed human ex vivo macrophages P2X receptor stimulation. MV was potently induced ATP the P2X7 agonist 3'-benzoylbenzoyl adenosine 5'-triphosphate, while it greatly reduced irreversible inhibitor-oxidized specific inhibitors KN-62, A-740003, A-438079. Peculiarly, subtype highly present in MVs, on contrary P2X3 P2X4 subtypes were almost absent. Ca(2+) ionophore A23187 mimicked effect of 5'-triphosphate suggesting intracellular increase sufficient to evoke shedding. Caspase Ac-YVAD-CMK Z-YVAD-CMK did not block cleavage MV-associated pro-IL-18. Pro-IL-18 formation require pretreatment LPS, procytokine already unprimed decrease incubating LPS-binding antibiotic polymyxin B nor TLR-4 inhibitor CLI-095. These data reveal a nucleotide-based mechanism responsible for which is associated.