Inhibition of lipopolysaccharide-induced nitric oxide synthesis by nicotine through S6K1-p42/44 MAPK pathway and STAT3 (Ser 727) phosphorylation in Raw 264.7 cells

Shin Young Park, Yong Hae Baik, Ju Hwan Cho, Sung Kim, Ki Sung Lee, Joong Soo Han

Research output: Contribution to journalArticle

32 Scopus citations

Abstract

Lipopolysaccharide (LPS) has been known to produce inflammatory modulators such as tumor necrosis factor α (TNF-α) or nitric oxide (NO). In this study, we examined the effects of nicotine on LPS enhanced NO synthesis and inducible nitric oxide synthase (iNOS) expression in macrophages. LPS-induced NO synthesis and iNOS expression were significantly decreased by nicotine. To investigate the signaling mechanism of nicotine induced suppression of NO synthesis and iNOS expression induced by LPS, we focused on the possible roles of p42/44 MAPK, S6K1, and signal transducers and activators of transcription 3 (STAT3) signaling. LPS is known to activate p42/44 MAPK and S6K1, which in turn activates STAT3 to induce inflammatory regulators. Pretreatment of cells with nicotine blocked LPS-induced p42/44 MAPK and S6K1 as well as iNOS promoter activity. Furthermore, we found that LPS-induced phosphorylation of STAT3 at serine 727 is mediated by S6K1-p42/44 MAPK pathway, and this STAT3 phosphorylation was also blocked by nicotine. We also found that downregulation of STAT3 using STAT3 siRNA resulted in suppression of the NO synthesis and iNOS expression. Taken together, our results suggest that nicotine inhibits LPS-induced NO synthesis through suppression of S6K1-p42/44 MAPK pathway and phosphorylation of STAT3 in Raw 264.7 cells.

Original languageEnglish
Pages (from-to)126-134
Number of pages9
JournalCytokine
Volume44
Issue number1
DOIs
StatePublished - 2008 Oct 1

Keywords

  • Lipopolysaccharide
  • Nicotine
  • Nitric oxide
  • S6K1
  • STAT3

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