BackgroundAnesthetic propofol has immunomodulatory effects, particularly in the area of anti-inflammation. Bacterial endotoxin lipopolysaccharide (LPS) induces inflammation through toll-like receptor (TLR) 4 signaling. We investigated the molecular actions of propofol against LPS/TLR4-induced inflammatory activation in murine RAW264.7 macrophages.Methodology/Principal FindingsNon-cytotoxic levels of propofol reduced LPS-induced inducible nitric oxide synthase (iNOS) and NO as determined by western blotting and the Griess reaction, respectively. Propofol also reduced the production of tumor necrosis factor-α (TNF-α), interleukin (IL)-6, and IL-10 as detected by enzyme-linked immunosorbent assays. Western blot analysis showed propofol inhibited LPS-induced activation and phosphorylation of IKKβ (Ser180) and nuclear factor (NF)-κB (Ser536); the subsequent nuclear translocation of NF-κB p65 was also reduced. Additionally, propofol inhibited LPS-induced Akt activation and phosphorylation (Ser473) partly by reducing reactive oxygen species (ROS) generation; inter-regulation that ROS regulated Akt followed by NF-κB activation was found to be crucial for LPS-induced inflammatory responses in macrophages. An in vivo study using C57BL/6 mice also demonstrated the anti-inflammatory properties against LPS in peritoneal macrophages.Conclusions/SignificanceThese results suggest that propofol reduces LPS-induced inflammatory responses in macrophages by inhibiting the interconnected ROS/Akt/IKKβ/NF-κB signaling pathways.

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there is a link between autophagy and both IFN-␥ signaling and cellular inflammation and that autophagy, because it inhibits the expression of reactive oxygen species and SHP2, is pivotal for Jak2-STAT1 activation.Autophagy, or autophagocytosis, is required for cellular regulation in response to a variety of stimuli, including starvation, pathogen-associated molecular patterns that are recognized by pattern-recognition receptors such as Toll-like receptors, and cytokines such as tumor necrosis factor (TNF)-␣ and interferon (IFN)-␥ (1, 2). In addition to maintaining cell survival and metabolic homeostasis (3), autophagy provides a cell-autonomous defense system for recognizing viral infections (4, 5) and eliminating intracellular pathogens via the autophagosome-lysosome pathway (6 -8).Proinflammatory cytokine IFN-␥, a type II IFN produced by T cells and natural killer cells, is involved in promoting diverse bioactivities, including antigen processing, intracellular microbial killing, and proinflammation (9). After binding with IFN-␥ receptors (IFNGRs), 2 IFN-␥ typically activates Jak2-STAT1 signaling and then regulates its bioactivities. For Jak2-STAT1 activation, Jak2 is first autophosphorylated at its tyrosine residues (Tyr 1007 /Tyr 1008 ) and then leads to Jak1 transphosphorylation (Tyr 1022 /Tyr 1023 ). The activation of Jak1 then phosphorylates IFNGR1 (Tyr 440 ), which induces the recruitment and activation of STAT1 through Jak2-mediated phosphorylation (Tyr 701 ). SOCS1 (suppressor of cytokine signaling-1), SOCS3, and SHP2 (dual-phosphatase Src homology-2 domain-containing phosphatase) provide feedback regulation by suppressing Jak2-STAT1 signaling (9, 10). SOCS1 and SOCS3 interact with IFNGRs, and SHP2 causes the dephosphorylation of Jak2 and STAT1. IFN-␥ induces, STAT1-dependently, SOCS1 and SOCS3 expression; however, the mechanisms for SHP2 activation remain undocumented.IFN-␥ uses a process that involves autophagy to increase the eradication of intracellular mycobacteria and chlamydia (6, 11). IFN-inducible immunity-related GTPases (Irgs (immunoreactive glucagons)), such as Irgm1 and Irga6 (6, 11), and IFN-inducible eukaryotic initiation factor (eIF)-2␣ kinase, protein kinase R (12), are potential autophagic regulators; however, the mechanisms for IFN-␥-induced autophagy are currently undocumented. In addition, the functions of autophagic machinery for IFN-␥-activated Jak2-STAT1 signaling and bioactivities require further investigation. In this study, we examined the role of autophagy and its molecular actions in the IFN-␥-induced Jak2-STAT1 activation and cellular inflammation. EXPERIMENTAL PROCEDURES

Enterovirus 71 (EV71) infection causes severe mortality involving multiple possible mechanisms, including cytokine storm, brain stem encephalitis, and fulminant pulmonary edema. Gamma interferon (IFN-␥) may confer anti-EV71 activity; however, the claim that disease severity is highly correlated to an increase in IFN-␥ is controversial and would indicate an immune escape initiated by EV71. This study, investigating the role of IFN-␥ in EV71 infection using a murine model, showed that IFN-␥ was elevated. Moreover, IFN-␥ receptor-deficient mice showed higher mortality rates and more severe disease progression with slower viral clearance than wild-type mice. E nterovirus 71 (EV71) is a single-stranded RNA virus in the Picornaviridae family. The EV71 genome encodes four structural proteins, VP1 to VP4, and seven nonstructural proteins, 2A to 2C and 3A to 3D (1). Numerous studies have investigated the functions of viral proteins in viral replication and virulence (2). During EV71 infection, capsid VP proteins mediate virus entry by binding to cellular receptors, human scavenger receptor class B and P-selectin glycoprotein ligand 1 (3). Additionally, VP proteins participate in the assembly of viral particles (4). The 3C protein, a chymotrypsin-like protease, reduces host cell transcription dramatically by inhibiting cell polyadenylation (5) and induces caspase-regulated neural cell apoptosis (6). To develop specific anti-EV71 drugs, a number of small molecules targeting viral proteins have been designed, such as the 3C inhibitor rupintrivir and the 3D inhibitor aurintricarboxylic acid (ATA) (7-9).EV71 infection typically causes mild, self-limiting hand-footand-mouth disease; however, patients sometimes have significant morbidity and mortality resulting from hemorrhagic pulmonary edema following acute central nervous system-related cardiopulmonary failure and brain stem encephalitis (2,10,11). In addition to the direct cytotoxicity caused by EV71 infection (12-16) and the resultant virulence factors (6, 17), host factors such as the aberrant production of cytokines that is detected during EV71-associated pulmonary edema can also lead to disease. In infected

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