Substance P-stimulated interleukin-8 expression in human colonic epithelial cells involves Rho family small GTPases

Dezheng Zhao, Sabina Kuhnt-Moore, Huiyan Zeng, Amy Pan, Jack S. Wu, Simos Simeonidis, Mary P. Moyer, Charalabos Pothoulakis

Research output: Contribution to journalArticlepeer-review

70 Scopus citations

Abstract

Interaction of the neuropeptide substance P (SP) and its neurokinin-1 receptor (NK-1R) plays an important role in the pathophysiology of intestinal inflammation. SP is known to stimulate production of interleukin (IL)-6 and IL-8 in the U-373-MG human astrocytoma cell line via activation of p38 MAPK (mitogen-activated protein kinase) and nuclear factor (NF)-κB, respectively. However, the signalling mechanisms by which SP-NK-1R interaction induces NF-κB activation and IL-8 expression are still not clear. In this study we demonstrate that SP stimulates IL-8 secretion and IL-8 promoter activity in the NCM460 non-transformed human colonic epithelial cell line transfected with NK-1R cDNA. Our results indicate that inhibition of endogenous Rho family proteins (RhoA, Rac1 and Cdc42) by their respective dominant negative mutants significantly decreases SP-induced IL-8 secretion and IL-8 promoter activity. We also demonstrate that SP rapidly activates RhoA, Rac1 and Cdc42 and that co-expression of the dominant negative mutants of RhoA, Rac1 and Cdc42 in NK-1R cDNA-transfected NCM460 cells significantly inhibits SP-induced NF-κB-dependent gene expression. These results demonstrate that Rho family small GTPases RhoA, Rac1 and Cdc42 are novel signal transducers for SP-stimulated IL-8 expression.

Original languageEnglish (US)
Pages (from-to)665-672
Number of pages8
JournalBiochemical Journal
Volume368
Issue number2
DOIs
StatePublished - Dec 1 2002
Externally publishedYes

Keywords

  • G-protein-coupled receptor
  • Inflammation
  • Neuropeptide
  • Signal transduction

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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