Luteolin inhibits viral-induced inflammatory response in RAW264.7 cells via suppression of STAT1/3 dependent NF-κB and activation of HO-1

Free Radic Biol Med. 2016 Jun;95:180-9. doi: 10.1016/j.freeradbiomed.2016.03.019. Epub 2016 Mar 23.

Abstract

Luteolin is a common dietary flavonoid present in Chinese herbal medicines that has been reported to have important anti-inflammatory properties. Previous studies have shown that luteolin is an anti-inflammatory and anti-oxidative agent. In this study, the anti-virus inflammatory capacity of luteolin and its molecular mechanisms of action were analyzed. The cytotoxic effects of luteolin were assessed in the presence or absence of pseudorabies virus (PRV) via LDH and MTT assays. The results showed that luteolin (<10μM) had no toxic effects and there were tendencies toward higher cell survival. In PRV-infected RAW264.7 cells, luteolin potently inhibited the production of NO, iNOS, COX-2 and inflammatory cytokine production. Luteolin did not inhibit the phosphorylation of ERK 1/2, p38, and JNK 1/2 either. We found that PRV-induced NF-κB activation is regulated through inhibition of STAT1and STAT3 phosphorylation in response to luteolin. Additionally, luteolin caused the induction of HO-1 via upregulation of Nrf2, both of which are involved in the secretion of proinflammatory mediators. The blockade of HO-1 expression with SnPP, a HO-1 inhibitor, attenuated HO-1 induction by luteolin and thus mitigated its anti-inflammatory effects during PRV-infected RAW264.7 cells. Taken together, our data indicate that luteolin diminishes the proinflammatory mediators NO, inflammatory cytokines and the expression of their regulatory genes, iNOS and COX-2, in PRV-infected RAW264.7 cells by inhibiting STAT1/3 dependent NF-κB activation and inducing Nrf2mediated HO-1 expression.

Keywords: HO-1; Luteolin; NF-κB; Nrf2; Pseudorabies virus (PRV); STAT1/3.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antioxidants / administration & dosage
  • Drugs, Chinese Herbal / administration & dosage
  • Gene Expression Regulation / drug effects
  • Heme Oxygenase-1 / genetics*
  • Herpesvirus 1, Suid / pathogenicity
  • Inflammation / drug therapy*
  • Inflammation / genetics
  • Inflammation / virology
  • Luteolin / administration & dosage*
  • Membrane Proteins / genetics*
  • Mice
  • NF-E2-Related Factor 2 / genetics
  • NF-kappa B / genetics
  • Phosphorylation / drug effects
  • RAW 264.7 Cells
  • STAT1 Transcription Factor / genetics*
  • STAT3 Transcription Factor / genetics*

Substances

  • Antioxidants
  • Drugs, Chinese Herbal
  • Membrane Proteins
  • NF-E2-Related Factor 2
  • NF-kappa B
  • Nfe2l2 protein, mouse
  • STAT1 Transcription Factor
  • STAT3 Transcription Factor
  • Stat1 protein, mouse
  • Stat3 protein, mouse
  • Heme Oxygenase-1
  • Hmox1 protein, mouse
  • Luteolin