Sera from Septic Patients Contain the Inhibiting Activity of the Extracellular ATP-Dependent Inflammasome Pathway.
Immunoparalysis is a common cause of death for critical care patients with sepsis, during which comprehensive suppression of innate and adaptive immunity plays a significant pathophysiological role. Although the underlying mechanisms are unknown, damage-associated molecular patterns (DAMPs) from septic tissues might be involved. Therefore, we surveyed sera from septic patients for factors that suppress the innate immune response to DAMPs, including adenosine triphosphate (ATP), monosodium urate, and high mobility group box-1. Macrophages, derived from THP-1 human acute monocytic leukemia cells, were incubated with each DAMP, in the presence or absence of sera that were collected from critically ill patients. Secreted cytokines were then quantified, and cell lysates were assayed for relevant intracellular signaling mediators. Sera from septic patients who ultimately did not survive significantly suppressed IL-1β production only in response to extracellular ATP. This effect was most pronounced with sera collected on day 3, and persisted with sera collected on day 7. However, this effect was not observed when THP-1 cells were treated with sera from survivors of sepsis. Septic sera collected at the time of admission (day 1) also diminished intracellular levels of inositol 1,4,5-triphosphate and cytosolic calcium (P < 0.01), both of which are essential for ATP signaling. Finally, activated caspase-1 was significantly diminished in cells exposed to sera collected on day 7 (P < 0.05). In conclusion, the sera of septic patients contain certain factors that persistently suppress the immune response to extracellular ATP, thereby leading to adverse clinical outcomes.
['Ho|Van Minh|VM|', 'Hirohashi|Nobuyuki|N|', 'Kong|Weng-Sheng|WS|', 'Yun|Guo|G|', 'Ota|Kohei|K|', 'Itai|Junji|J|', 'Yamaga|Satoshi|S|', 'Suzuki|Kei|K|', 'Tanigawa|Koichi|K|', 'Kanno|Masamoto|M|', 'Shime|Nobuaki|N|']
D000251:Adenosine Triphosphatases D000255:Adenosine Triphosphate D000368:Aged D000067531:Alarmins D016022:Case-Control Studies D020170:Caspase 1 D018925:Chemokines D015331:Cohort Studies D004789:Enzyme Activation D005110:Extracellular Space D005260:Female D006801:Humans D058847:Inflammasomes D007249:Inflammation D053583:Interleukin-1beta D008264:Macrophages D008297:Male D058486:Receptors, Purinergic P2X7 D018805:Sepsis D015398:Signal Transduction
immunoparalysis sepsis damage-associated molecular patterns innate immune response extracellular adenosine triphosphate