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. 2009 Jan 26;119(2):305–314. doi: 10.1172/JCI35958

Figure 3. DNA from apoptotic hepatocytes increases pro–IL-1β and pro–IL-18 transcript levels in primary liver endothelial cells, and this is inhibited by Tlr9 antagonist.

Figure 3

(A and B) To determine whether APAP-induced upregulation of pro–IL-1β and pro–IL-18 was dependent on immune cells, we examined the livers of Rag1–/–γ–/– mice, which lack most immune cell populations. There was significant upregulation of the transcripts of both cytokines in the livers of Rag1–/–γ–/– mice (*P < 0.001 and **P < 0.01). (C and D) Culture of primary mouse endothelial cells from Tlr9+/+ mice with DNA from apoptotic (APOP) but not healthy hepatocytes results in upregulation of pro–IL-1β and pro–IL-18, and this is downregulated by Tlr9 antagonist ODN2088 (*P < 0.001). (E and F) Culture of mouse endothelial cells from Tlr9–/– mice with DNA from apoptotic and healthy hepatocytes does not result in upregulation of pro–IL-1β and pro–IL-18. (G) To establish the importance of IL-1β in APAP hepatotoxicity, an anti–IL-1β antibody (0.2 mg per mouse) was used for in vivo neutralization. This demonstrates a significant increase in survival of wild-type mice in the presence of IL-1β neutralization compared with control antibody after APAP (control antibody: n = 10, anti–IL-1β: n = 10, P < 0.02). (H) To establish the importance of IL-18 in APAP hepatotoxicity, we treated Il18–/– and Il18+/+ mice with APAP. There was significantly better survival in Il18–/– compared with Il18+/+ mice (Il18+/+: n = 10, Il18–/–: n = 7, P < 0.036). Error bars indicate 1 SD.