Methane alleviates carbon tetrachloride induced liver injury in mice: anti-inflammatory action demonstrated by increased PI3K/Akt/GSK-3β-mediated IL-10 expression

Abstract

The inflammatory response plays an important role in carbon tetrachloride (CCl)-induced acute liver injury and methane has been shown to exert beneficial effects on inflammation-associated diseases. Thus, we investigated the potential protective effects of methane-rich saline (MS) on CCl-induced acute liver injury and explored the underlying mechanism. A CCl-induced acute liver injury model was established by injection of CCl (0.6 ml/kg, ip) in mice followed by treatment with MS (16 ml/kg, ip), 24 h later. All groups of mice were sacrificed and blood and liver tissues were collected. Serum aminotransferase, necrotic areas, and inflammatory cell infiltration in liver slices were enhanced after CCl treatment but decreased with MS treatment. IL-6, TNF-α, IL-1β, IFN-γ, ICAM-1, CXCL1, MPO, NF-κB p65, ERK, JNK, and MAPK P38, expression in serum or liver homogenate were greater after CCl treatment but comparatively less after MS treatment. Only IL-10 increased after MS treatment. Anti-IL10 blockade (1.5 mg/kg) restored MS-mediated attenuated phosphorylation of NF-ĸbB/MAPK and the protective effect of MS was abolished for all indices examined. The PI3K inhibitor, wortmannin had the same effects on MS as anti-IL-10 antibody. MS also induced phosphorylation of GSK-3β and AKT in CCl-treated mice. After pre-treatment with wortmannin (0.7 mg/kg), phosphorylation of GSK-3β and AKT proteins were reduced compared to its solvent control group-DMSO-treated animals. Thus, the data provide evidence that MS may activate the PI3K-AKT-GSK-3β pathway to induce IL-10 expression and produce anti-inflammatory effects via the NF-κB and MAPK pathways. The findings provide a new pharmacological strategy for management of inflammatory response after acute liver injury.

Protective Effect of Eckol against Acute Hepatic Injury Induced by Carbon Tetrachloride in Mice

“…Additionally, CCl 4 -induced elevations of pro-inflammatory cytokines TNF-α, IL-1β and IL-6 were markedly suppressed in the eckol-treated group ( p < 0.01, vs. CCl 4 model group). However, eckol further notably enhanced the level of IL-10 ( p < 0.01, vs. CCl 4 model group), a potent anti-inflammatory cytokine which plays a critical role in natural defense against detrimental immune/inflammatory responses [ 29 ], which was different from the positive control bifendate.…”

“…The above finding, that eckol exhibited the activity of upregulating endogenous production of the anti-inflammatory cytokine IL-10, attracted our attention. In fact, exogenous administration of IL-10 has long been demonstrated to protect the liver from toxic damage caused by a number of insults [ 29 ]. It has been well-accepted that most of the inflammatory liver diseases are immune-mediated [ 30 ].…”

Glycyrrhizic Acid Prevents Diabetic Nephropathy by Activating AMPK/SIRT1/PGC-1α Signaling in db/db Mice

“…Glycyrrhizic acid (GA) is a triterpenoid saponin glycoside that is known as the most efficacious component of the licorice plant [ 9 , 10 ]. Previous studies have shown that GA exhibits antiulcerative, expectorant, antiviral, anti-inflammatory, antidiabetic, anticancer, neuroprotective, and immune-enhancing properties [ 11 , 12 ].…”

Reduction of perioperative inflammatory reaction with exogenous methane

“…Although CH4 is widely regarded as inactive, a number of studies have demonstrated explicit biological effects in living biological systems (10). An anti-inflammatory potential for CH4 was first reported in a canine model of intestinal ischaemia-reperfusion (I-R) (11), and thereafter other reports have confirmed the antioxidant and anti-apoptotic effects of exogenous CH4 administration in various in vitro and in vivo settings (12)(13)(14)(15)(16)(17)(18)(19)(20)(21). The exact mechanism of action is not fully clarified, but it has been shown that the anti-inflammatory action is mediated through the inhibition of polymorphonuclear (PMN) leukocyte activation and reduced reactive oxygen species (ROS) production (11).…”

“…Other findings provided evidence that administration of CH4-enriched saline solutions is protective in experimental liver failure (12), autoimmune hepatitis (23), acute lung injury (15), and hepatic (13), spinal cord (15), retinal (16), myocardial (17) and skin I-R injuries (18). Today the overall evidence points to the likelihood that exogenous CH4 can influence different intracellular signalling pathways, which may be therapeutically exploited to attenuate the signs and consequences of inflammation (24).…”