Skip to main content

Advertisement

SpringerLink
Log in

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

  • Original Paper
  • Published:
Journal of Molecular Histology Aims and scope Submit manuscript

Abstract

The inflammatory response plays an important role in carbon tetrachloride (CCl4)-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 CCl4-induced acute liver injury and explored the underlying mechanism. A CCl4-induced acute liver injury model was established by injection of CCl4 (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 CCl4 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 CCl4 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 CCl4-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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  • Abdel-Moneim AM, Al-Kahtani MA, El-Kersh MA et al (2015) Free radical-scavenging, anti-inflammatory/anti-fibrotic and hepatoprotective actions of taurine and silymarin against CCl4 induced rat liver damage. PLoS ONE 10:e0144509

    Article  PubMed  PubMed Central  Google Scholar 

  • Ananieva O et al (2008) The kinases MSK1 and MSK2 act as negative regulators of Toll-like receptor signaling. Nat Immunol 9:1028–1036

    Article  CAS  PubMed  Google Scholar 

  • Bekker Z, Walubo A, Du Plessis JB et al (2016) Changes in IL-2 and IL-10 during Chronic Administration of Isoniazid, Nevirapine, and Paracetamol in Rats. Adv Pharmacol Sci 11:3094783

    Google Scholar 

  • Beurel E, Michalek SM, Jope RS et al (2010) Innate and adaptive immune responses regulated by glycogen synthase kinase-3 (GSK3). Trends Immunol 31:24–31

    Article  CAS  PubMed  Google Scholar 

  • Beurel E, Grieco SF, Jope RS et al (2015) Glycogen synthase kinase-3 (GSK3): regulation, actions, and diseases. Pharmacol Ther 148:114–131

    Article  CAS  PubMed  Google Scholar 

  • Boros M, Ghyczy M, Érces D et al (2012) The anti-inflammatory effects of methane. Crit Care Med 4:1269–1278

    Article  Google Scholar 

  • Cao S, Zhang X, Edwards JP, Mosser DM (2006) NF-kappaB1 (p50) homodimers differentially regulate pro- and anti-inflammatory cytokines in macrophages. J Biol Chem 281:26041–26050

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chen O, Ye Z, Cao Z et al (2015) Methane attenuates myocardial ischemia injury in rats through anti-oxidative, anti-apoptoticand anti-inflammatory actions, Free Radic Biol Med 90:1–11

    Article  PubMed  Google Scholar 

  • Douglas DB, Beiting DP, Loftus JP et al (2010) Combinatorial effects of interleukin 10 and interleukin 4 determine the progression of hepatic inflammation following murine enteric parasitic infection. Hepatology 51:2162–2171

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Erhardt A, Biburger M, Papadopoulos T et al (2007) IL-10, regulatory T cells, and Kupffer cells mediate tolerance in concanavalin A-induced liver injury in mice. Hepatology 45:475–485

    Article  CAS  PubMed  Google Scholar 

  • Fan DF, Hu HJ, Sun Q et al (2016) Neuroprotective effects of exogenous methane in a rat model of acute carbon monoxide poisoning. Brain Res 1633:62–72

    Article  CAS  PubMed  Google Scholar 

  • Gabrysova L, Howes A, Saraiva M et al (2014) The regulation of IL-10 expression. Curr Top Microbiol Immunol 380:157–190

    CAS  PubMed  Google Scholar 

  • Ghoshal U, Shukla R, Srivastava D et al (2016) Irritable bowel syndrome, particularly the constipation-predominant form, involves an increase in methanobrevibacter smithii, which is associated with higher methane production. Gut Liver 6:932–938

    Article  Google Scholar 

  • Ghyczy M et al (2008) Hypoxia-induced generation of methane in mitochondria and eukaryotic cells: an alternative approach to methanogenesis. Cell Physiol Biochem 21:251–258

    Article  CAS  PubMed  Google Scholar 

  • He R, Wang L, Zhu J et al (2016) Methane-rich saline protects against concanavalin A-induced autoimmune hepatitis in mice through anti-inflammatory and anti-oxidative pathways. Biochem Biophys Res Commun 1:22–28

    Article  Google Scholar 

  • Hovsepian E, Siffo S, Mirkin GA et al (2013) IL-10 inhibits the NF-ĸB and ERK/MAPK-mediated production of pro-inflammatory mediators by up-regulation of SOCS-3 in Trypanosoma cruzi-infected cardiomyocytes. PLoS ONE 8:e79445

    Article  PubMed  PubMed Central  Google Scholar 

  • Juhaszova M, Zorov DB, Kim SH et al (2004) Glycogen synthase kinase-3beta mediates convergence of protection signaling to inhibit the mitochondrial permeability transition pore. J Clin Invest 113:1535–1549

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kai T, Jones KA, Warner DO et al (1998) Halothane attenuates calcium sensitization in airway smooth muscle by inhibiting G-proteins. Anesthesiology 89:1543–1552

    Article  CAS  PubMed  Google Scholar 

  • Liu L, Sun Q, Wang R et al (2016) Methane attenuates retinal ischemia/reperfusioninjury via anti-oxidative and anti-apoptotic pathways. Brain Res 1646:327–333

    Article  CAS  PubMed  Google Scholar 

  • Mackenzie KF, Clark K, Naqvi S, Mcguire VA et al (2013) PGE(2) induces macrophage IL-10 production and a regulatory-like phenotype via a protein kinase A-SIK-CRTC3 pathway. J Immunol 190:565–577

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • MacKenzie KF et al (2013) PGE(2) induces macrophage IL-10 production and a regulatory-like phenotype via a protein kinase A-SIK-CRTC3 pathway. J Immunol 190:565–577

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Maes M, Vinken M, Jaeschke H et al (2016) Experimental models of hepatotoxicity related to acute liver failure. Toxicol Appl Pharmacol 290:86–97

    Article  CAS  PubMed  Google Scholar 

  • Magaye R, Gu Y, Wang Y et al (2016) In vitro and in vivo evaluation of the toxicities induced by metallic nickel nano and fine particles. J Mol Histol 47:273–286

    Article  CAS  PubMed  Google Scholar 

  • Martin M, Rehani K, Jope RS et al (2005) Toll-like receptor-mediated cytokine production is differentially regulated by glycogen synthase kinase 3. Nat Immunol 6:777–784

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Martin M, Mory C, Prescher A et al (2010) Protective effects of early CD4(+) T cell reduction in hepatic ischemia/reperfusion injury. J Gastrointest Surg 14:511–519

    Article  PubMed  Google Scholar 

  • Mittal SK, Roche PA (2015) Suppression of antigen presentation by IL-10. Curr Opin Immunol 34:22–27

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mizuoka H, Shikata N, Yang J et al (1999) Biphasic effect of colchicine on acute liver injury induced by carbon tetrachloride or by dimethylnitrosamine in mice. J Hepatol 31:825–833

    Article  CAS  PubMed  Google Scholar 

  • Montano-Loza AJ, Bhanji RA, Wasilenko S et al (2017) Systematic review: recurrent autoimmune liver diseases after liver transplantation. Aliment Pharmacol Ther 45:485–500

    Article  CAS  PubMed  Google Scholar 

  • Nandan D et al (2012) Myeloid cell IL-10 production in response to leishmania involves inactivation of glycogen synthase kinase-3beta downstream of phosphatidylinositol-3 kinase. J Immunol 188:367–378

    Article  CAS  PubMed  Google Scholar 

  • Ouyang W, Rutz S, Crellin NK et al (2011) Regulation and functions of the IL-10 family of cytokines in inflammation and disease. Annu Rev Immunol 29:71–109

    Article  CAS  PubMed  Google Scholar 

  • Özdemir-Kumral ZN, Özbeyli D, Özdemir AF et al (2016) Protective effect of nicotine on sepsis-induced oxidative multiorgan damage: role of neutrophils. Nicotine Tob Res 2017(7):859–864

    Google Scholar 

  • Peng XD, Dai LL, Huang CQ et al (2009) Relationship between anti-fibrotic effect of Panax notoginsengsaponins and serum cytokines in rat hepatic fibrosis. BiochemBiophys Res Commun 388:31–34

    Article  CAS  Google Scholar 

  • Pimentel M et al (2006) Methane, a gas produced by enteric bacteria, slows intestinal transit and augments small intestinal contractile activity. Am J Physiol Gastrointest Liver Physiol 290:G1089–G1095

    Article  CAS  PubMed  Google Scholar 

  • Puig MM, Warner W, Tang CK, Lovitz M, Turndorf H et al (1988) Synergistic interaction of morphine and halothane in the guinea pig ileum. Anesthesiology 68:559–562

    Article  CAS  PubMed  Google Scholar 

  • Ren F, Duan Z, Cheng Q et al (2011) Inhibition of glycogen synthase kinase 3 beta ameliorates liver ischemia reperfusion injury by way of an interleukin-10-mediated immune regulatory mechanism. Hepatology 54:687–696

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Roccarina D, Lauritano EC, Gabrielli M et al (2010) The role of methane in intestinal diseases. Am J Gastroenterol 105:1250–1256

    Article  PubMed  Google Scholar 

  • Rood JE, Canna SW, Weaver LK et al (2016) IL-10 distinguishes a unique population of activated, effector-like CD8+ T cells in murine acute liverinflammation. J Leukoc Biol 2017(4):1037–1044

    Google Scholar 

  • Sanin DE, Prendergast CT, Mountford AP et al (2015) IL-10 production in macrophages is regulated by a TLR-driven CREB-mediated mechanism that is linked to genes involved in cell metabolism. J Immunol 195:1218–1232

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schwabe RF, Brenner DA et al (2002) Role of glycogen synthase kinase-3 in TNF-alpha-induced NF-kappaB activation and apoptosis in hepatocytes. Am J Physiol Gastrointest Liver Physiol 283:G204–G211

    Article  CAS  PubMed  Google Scholar 

  • Shao X, Qian Y, Xu C et al (2013) The protective effect of intrasplenic transplantation of Ad-IL-18BP/IL-4 gene-modified fetal hepatocytes on ConA-induced hepatitis in mice. PLoS ONE 8:e58836

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Si ZZ, Li JQ, Qi HZ et al (2010) Recombinant adenovirus vector AdhIL-10 protects grafts from cold ischemia-reperfusion injury following orthotopic liver transplantation in rats. Hepatobiliary Pancreat Dis Int 9:144–148

    CAS  PubMed  Google Scholar 

  • Sokoll MD, Davies LR, Bhattacharyya B, Zwagerman DQ et al (1989) Halothane and isoflurane alter acetylcholine activated ion channel kinetics. Eur J Pharmacol 173:27–34

    Article  CAS  PubMed  Google Scholar 

  • Song K, Zhang M, Hu J et al (2015) Methane-rich saline attenuates ischemia/reperfusion injury of abdominal skin flaps in rats via regulating apoptosis level. BMC Surg 15:92

    Article  PubMed  PubMed Central  Google Scholar 

  • Strifler G, Tuboly E, Szél E et al (2016) Inhaled methane limits the mitochondrial electron transport chain dysfunction during experimental liver ischemia-reperfusion injury. PLoS ONE 1:e0146363

    Article  Google Scholar 

  • Szabo G, Petrasek J (2015) Inflammasome activation and function in liver disease. Nat Rev Gastroenterol Hepatol 7:387–400

    Article  Google Scholar 

  • Varga G, Erces D, Tuboly E et al (2012) Characterization of the anti-inflammatory properties of methane inhalation during ischaemia-reperfusion. Magy Seb 4:205–211

    Article  Google Scholar 

  • Venardos KM, Perkins A, Headrick J, Kaye DM et al (2007) Myocardial ischemia-reperfusion injury, antioxidant enzyme systems, and selenium: a review. Curr Med Chem 14:1539–1549

    Article  CAS  PubMed  Google Scholar 

  • Viatour P et al (2004) GSK3-mediated BCL-3 phosphorylation modulates its degradation and its oncogenicity. Mol Cell 16:35–45

    Article  CAS  PubMed  Google Scholar 

  • Wang L, Yao Y, He R et al (2016) Methane ameliorates spinal cord ischemia-reperfusion injury in rats: antioxidant, anti-inflammatory and anti-apoptotic activity mediated by Nrf2 activation. Free Radic Biol Med 103:69–86

    Article  PubMed  Google Scholar 

  • Wu J, Wang R, Ye Z et al (2015) Protective effects of methane-rich saline on diabetic retinopathy via anti-inflammation in a streptozotocin-induced diabetic rat model. Biochem Biophys Res Commun 2:155–161

    Article  Google Scholar 

  • Yao Y, Simard AR, Shi FD et al (2013a) IL-10-producing lymphocytes in inflammatory disease. Int Rev Immunol 32:324–336

    Article  CAS  PubMed  Google Scholar 

  • Yao Y, Simard AR, Shi F (2013b) D.et al, IL-10-producing lymphocytes in inflammatory disease. Int Rev Immunol 32:324–336

    Article  CAS  PubMed  Google Scholar 

  • Ye Z, Chen O, Zhang R et al (2015) Methane attenuates hepatic ischemia/reperfusion injury in rats through antiapoptotic, anti-inflammatory, and antioxidative actions. Shock 44:181–187

    Article  CAS  PubMed  Google Scholar 

  • Zhang X, Li N, Shao H et al (2016) Methane limit LPS-induced NF-ĸB/MAPKs signal in macrophages and suppress immune response in mice by enhancing PI3K/AKT/GSK-3β-mediated IL-10 expression. Sci Rep 6:29359

    Article  PubMed  PubMed Central  Google Scholar 

  • Zhao X, Shi X, Zhang Z et al (2016) Combined treatment with MSC transplantation and neutrophil depletion ameliorates D-GalN/LPS -induced acute liver failure in rats. Clin Res Hepatol Gastroenterol 6:730–738

    Article  Google Scholar 

Download references

Acknowledgements

This work was supported by National Natural Science Foundation (81471845, 81671939) and Shanghai Scientific research project (15411963200).

Author information

Author notes

    Authors and Affiliations

    1. Department of Anesthesiology and Intensive Care, Changhai Hospital, Second Military Medical University, Shanghai, 200433, People’s Republic of China

      Ying Yao, Peipei Jin, Na Li, Yan Meng, Changli Wang, Mengda Xu, Yan Zhang, Jinjun Bian & Xiaoming Deng

    2. Department of Anesthesiology, Fuzhou General Hospital of PLA, Fuzhou, 350025, Fujian, People’s Republic of China

      Liping Wang

    Authors
    1. Ying Yao
      View author publications

      You can also search for this author in PubMed Google Scholar

    2. Liping Wang
      View author publications

      You can also search for this author in PubMed Google Scholar

    3. Peipei Jin
      View author publications

      You can also search for this author in PubMed Google Scholar

    4. Na Li
      View author publications

      You can also search for this author in PubMed Google Scholar

    5. Yan Meng
      View author publications

      You can also search for this author in PubMed Google Scholar

    6. Changli Wang
      View author publications

      You can also search for this author in PubMed Google Scholar

    7. Mengda Xu
      View author publications

      You can also search for this author in PubMed Google Scholar

    8. Yan Zhang
      View author publications

      You can also search for this author in PubMed Google Scholar

    9. Jinjun Bian
      View author publications

      You can also search for this author in PubMed Google Scholar

    10. Xiaoming Deng
      View author publications

      You can also search for this author in PubMed Google Scholar

    Corresponding authors

    Correspondence to Jinjun Bian or Xiaoming Deng.

    Ethics declarations

    Conflicts of interest

    All authors have no potential financial or ethical conflicts of interest regarding this paper.

    Additional information

    Ying Yao, Liping Wang and Peipei Jin have contributed equally to this work.

    Electronic supplementary material

    Below is the link to the electronic supplementary material.

    Supplementary material 1 (TIF 8220 KB)

    Rights and permissions

    Reprints and permissions

    About this article

    Check for updates. Verify currency and authenticity via CrossMark

    Cite this article

    Yao, Y., Wang, L., Jin, P. et al. Methane alleviates carbon tetrachloride induced liver injury in mice: anti-inflammatory action demonstrated by increased PI3K/Akt/GSK-3β-mediated IL-10 expression. J Mol Hist 48, 301–310 (2017). https://doi.org/10.1007/s10735-017-9728-1

    Download citation

    • Received:

    • Accepted:

    • Published:

    • Issue Date:

    • DOI: https://doi.org/10.1007/s10735-017-9728-1

    Keywords

    Search

    Navigation