Inhibition of curcumin on influenza A virus infection and influenzal pneumonia via oxidative stress, TLR2/4, p38/JNK MAPK and NF-κB pathways

Int Immunopharmacol. 2018 Jan:54:177-187. doi: 10.1016/j.intimp.2017.11.009. Epub 2017 Nov 15.

Abstract

Oxidative stress, Nrf2-HO-1 and TLR-MAPK/NF-κB signaling pathways have been proved to be involved in influenza A virus (IAV) replication and influenzal pneumonia. In the previous studies, we have performed several high-throughput drug screenings based on the TLR pathways. In the present study, through plaque inhibition test, luciferase reporter assay, TCID50, qRT-PCR, western blotting, ELISA and siRNA assays, we investigated the effect and mechanism of action of curcumin against IAV infection in vitro and in vivo. The results showed that curcumin could directly inactivate IAV, blocked IAV adsorption and inhibited IAV proliferation. As for the underlying mechanisms, we found that curcumin could significantly inhibit IAV-induced oxidative stress, increased Nrf2, HO-1, NQO1, GSTA3 and IFN-β production, and suppressed IAV-induced activation of TLR2/4/7, Akt, p38/JNK MAPK and NF-κB pathways. Suppression of Nrf2 via siRNA significantly abolished the stimulatory effect of curcumin on HO-1, NQO1, GSTA3 and IFN-β production and meanwhile blocked the inhibitory effect of curcumin on IAV M2 production. Oxidant H2O2 and TLR2/4, p38/JNK and NF-κB agonists could significantly antagonize the anti-IAV activity of curcumin in vitro. Additionally, curcumin significantly increased the survival rate of mice, reduced lung index, inflammatory cytokines and lung IAV titer, and finally improved pulmonary histopathological changes after IAV infection. In conclusion, curcumin can directly inactivate IAV, inhibits IAV adsorption and replication; and its inhibition on IAV replication may be via activating Nrf2 signal and inhibiting IAV-induced activation of TLR2/4, p38/JNK MAPK and NF-κB pathways.

Keywords: Curcumin; Influenza A virus; MAPK, NF-κB; Nrf2; TLRs.

MeSH terms

  • A549 Cells
  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal
  • Curcumin / therapeutic use*
  • Dogs
  • Female
  • Humans
  • Influenza A virus / physiology*
  • Influenza, Human / drug therapy*
  • Influenza, Human / immunology
  • JNK Mitogen-Activated Protein Kinases / metabolism
  • Madin Darby Canine Kidney Cells
  • Male
  • Mice
  • Mice, Inbred C57BL
  • NF-E2-Related Factor 2 / genetics
  • NF-E2-Related Factor 2 / metabolism*
  • Orthomyxoviridae Infections / drug therapy*
  • Orthomyxoviridae Infections / immunology
  • Oxidative Stress
  • Pneumonia / drug therapy*
  • Pneumonia / immunology
  • RNA, Small Interfering / genetics
  • Signal Transduction / drug effects
  • Toll-Like Receptor 2 / metabolism
  • Toll-Like Receptor 4 / metabolism
  • Transcription Factor RelA / metabolism
  • Virus Replication / drug effects
  • p38 Mitogen-Activated Protein Kinases / metabolism

Substances

  • Anti-Inflammatory Agents, Non-Steroidal
  • NF-E2-Related Factor 2
  • NFE2L2 protein, human
  • RELA protein, human
  • RNA, Small Interfering
  • TLR2 protein, human
  • TLR4 protein, human
  • Toll-Like Receptor 2
  • Toll-Like Receptor 4
  • Transcription Factor RelA
  • JNK Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases
  • Curcumin