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Subanesthetic isoflurane reduces zymosan-induced inflammation in murine Kupffer cells by inhibiting ROS-activated p38
Hui Wang1, Lei Wang1, Nan-lin Li1
1Department of Vascular and Endocrine Surgery, Xijing Hospital, Fourth Military Medical University, No. 15 Changle West Road, Xi'an, Shaanxi 710032, China.
Abstract:
Volatile anesthetic isoflurane (ISO) has immunomodulatory effects. The fungal component zymosan (ZY) induces inflammation through toll-like receptor 2 or dectin-1 signaling. We investigated the molecular actions of subanesthetic (0.7%) ISO against ZY-induced inflammatory activation in murine Kupffer cells (KCs), which are known as the resident macrophages within the liver. We observed that ISO reduced ZY-induced cyclooxygenase 2 upregulation and prostaglandin E2 release, as determined by western blot and radioimmunoassay, respectively. ISO also reduced the production of tumor necrosis factor-α, interleukin-1β, IL-6, high-mobility group box-1, macrophage inflammatory protein-1α, macrophage inflammatory protein-2, and monocyte chemoattractant protein-1 as assessed by enzyme-linked immunosorbent assays. ISO blocked the ZY-induced nuclear translocation and DNA-binding activity of nuclear factor- (NF)-κB p65. Moreover, ISO attenuated ZY-induced p38 mitogen-activated protein kinase (MAPK) activation partly by scavenging reactive oxygen species (ROS); the interregulation that ROS activated p38 MAPK followed by NF-κB activation was crucial for the ZY-induced inflammatory responses in KCs. An in vivo study by peritoneal injection of ZY into BALB/C mice confirmed the anti-inflammatory properties of 0.7% ISO against ZY in KCs. These results suggest that ISO ameliorates ZY-induced inflammatory responses in murine KCs by inhibiting the interconnected ROS/p38 MAPK/NF-κB signaling pathways.
Insights
Subanesthetic isoflurane (ISO) reduces inflammation in liver macrophages by inhibiting key signaling pathways. This volatile anesthetic demonstrates anti-inflammatory properties against fungal components in both cell cultures and live mice.
Area of Science:
- Immunology
- Anesthesiology
- Cell Biology
Background:
- Volatile anesthetic isoflurane (ISO) possesses immunomodulatory effects.
- Zymosan (ZY), a fungal component, triggers inflammation via toll-like receptor 2 or dectin-1 signaling.
- Kupffer cells (KCs) are resident liver macrophages crucial for hepatic immune responses.
Purpose of the Study:
- To investigate the molecular mechanisms by which subanesthetic ISO (0.7%) counteracts ZY-induced inflammatory activation in murine KCs.
- To elucidate the role of reactive oxygen species (ROS), p38 mitogen-activated protein kinase (MAPK), and nuclear factor-κB (NF-κB) signaling in ZY-induced inflammation and ISO's inhibitory effects.
Main Methods:
- Western blot and radioimmunoassay were used to measure cyclooxygenase 2 (COX-2) and prostaglandin E2 (PGE2) levels.
- Enzyme-linked immunosorbent assays (ELISAs) quantified the production of various pro-inflammatory cytokines and chemokines (TNF-α, IL-1β, IL-6, HMGB1, MIP-1α, MIP-2, MCP-1).
- Electrophoretic mobility shift assays (EMSAs) assessed NF-κB p65 DNA-binding activity, and in vivo studies in BALB/C mice confirmed findings.
Main Results:
- ISO significantly reduced ZY-induced COX-2 upregulation and PGE2 release.
- ISO suppressed the production of multiple inflammatory mediators, including TNF-α, IL-1β, IL-6, HMGB1, MIP-1α, MIP-2, and MCP-1.
- ISO inhibited ZY-induced NF-κB p65 nuclear translocation and DNA-binding activity.
- ISO attenuated ZY-induced p38 MAPK activation, partly through ROS scavenging, highlighting the ROS/p38 MAPK/NF-κB pathway's importance.
Conclusions:
- Subanesthetic ISO exhibits significant anti-inflammatory effects against ZY-induced activation in murine Kupffer cells.
- ISO ameliorates ZY-induced inflammation by inhibiting the interconnected ROS/p38 MAPK/NF-κB signaling pathways.
- These findings suggest potential therapeutic applications for ISO in managing inflammatory conditions involving fungal components or related pathways.
