Aims: Indentify the regulatory pathways for inflammasome activation. Methods: The caspase-1 inflammasome was activated by LPS and ATP in primary mouse macrophages, and the effect of adenosine
was assayed by quantifying IL-1β in the supernatant, and activated caspase-1 in cell lystaes. Further investigations were performed using receptor specific inhibitors, gene inactivation by knockout approach, adenylate cyclase MI-503 mouse and PKA inhibitors. Fibrosis was induced by TAA in the presence and absence of digoxin (1 mg/Kg ip). Results: Adenosine alone did not induce inflammasome activation as judged by IL-1 p production. Adenosine enhanced and antagonism of A2a receptor inhibited LPS/ATP activated inflammasome activation. This was further demonstrated to be dependent on the A2aR, adenylate cyclase, cAMP and PKA signaling, and GREB and HIF-1α transcriptional
program. Activation of the A2aR resulted in up-regulation of pro-IL-1β as well as greater cleavage of caspase-1. In the setting of lack of IL-1β responses after previous exposure to LPS, adenosine can supersede this tolerogenic state and drive IL-1β production. As predicted in mice lacking the A2a receptor on macrophages there was a reduction in immune mediated liver injury and fibrosis. Digoxin, A potent HIF-1α inhibitor, was able to inhibit inflammasome activation and reduce liver injury and fibrosis. Conclusions: We have characterized a previously unknown A2aR/HIF-α mediated pathway MCE with explains learn more how inflammasome activity is sustained after initial activation, and shown that digoxin can reduce liver injury and fibrosis. Disclosures:Bruce N. Cronstein – Advisory Committees or Review Panels: Bristol-Myers Squibb, Novartis, CanFite Biopharmaceuticals, Cypress Laboratories, Regeneron, Endocyte, Savient; Board
Membership: Vilcek Foundation; Consulting: Prometheus, Protalex, Williams & Connolly, LLP, Merck Serono; Grant/Research Support: OSI Pharmaceuticals, URL Pharmaceuticals; Patent Held/Filed: NYU School of Medicine/Multiple; Stock Shareholder: CanFite Biopharmaceuticals Wajahat Z. Mehal – Management Position: Gloabl BioReserach Partners The following people have nothing to disclose: Xinshou Ouyang, Ayaz Ghani, Ahsan F. Malik TNF signaling is important for host defense during microbial infection, however uncontrolled TNF response may lead to excessive inflammation and organ injury. TNFR-shedding contributes to counter-inflammatory responses; however the mechanism leading to TNFR-shedding is unknown. Our previous work showed that LPS induces shedding of TNFRI from mouse hepatocytes (HG) via iN〇S-cGMP-TAGE signaling in vivo and in vitro. Therefore, we hypothesized that modulation of HCTNFRI shedding may limit excessive inflammation during sepsis in vivo. In vivo, WT (G57BL/6), and iN〇SK〇 mice were subject to a polymicrobial sepsis model (cecum ligation and puncture, GLP) for 8h (n=6/gp).
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