Rotavirus NSP4 Triggers Secretion of Proinflammatory Cytokines from Macrophages via Toll-Like Receptor 2

J Virol. 2013 Oct;87(20):11160-7. doi: 10.1128/JVI.03099-12. Epub 2013 Aug 7.


Nonstructural protein 4 (NSP4), encoded by rotavirus, exhibits various properties linked to viral pathogenesis, including enterotoxic activity. A recent study (O. V. Kavanagh et al., Vaccine 28:3106-3111, 2010) indicated that NSP4 also has adjuvant properties, suggesting a possible role in the innate immune response to rotavirus infection. We report here that NSP4 purified from the medium of rotavirus-infected Caco-2 cells triggers the secretion of proinflammatory cytokines from macrophage-like THP-1 cells and nitric oxide from murine RAW 264.7 cells. Secretion is accompanied by the stimulation of p38 and JNK mitogen-activated protein kinases (MAPKs) and nuclear factor NF-κB. NSP4 triggered the secretion of cytokines from murine macrophages derived from wild-type but not MyD88(-/-) or Toll-like receptor 2 (TLR2(-/-)) mice and induced secretion of interleukin-8 (IL-8) from human embryonic kidney cells transfected with TLR2 but not TLR4. Our studies identify NSP4 as a pathogen-associated molecular pattern (PAMP) encoded by rotavirus and provide a mechanism for the production of proinflammatory cytokines associated with the clinical symptoms of infection in humans and animals.

MeSH terms

  • Animals
  • Cell Line
  • Cytokines / metabolism*
  • Glycoproteins / metabolism*
  • Host-Pathogen Interactions*
  • Humans
  • MAP Kinase Signaling System
  • Macrophages / immunology*
  • Macrophages / virology*
  • Mice
  • Mice, Knockout
  • NF-kappa B / metabolism
  • Rotavirus / immunology*
  • Toll-Like Receptor 2 / metabolism*
  • Toxins, Biological / metabolism*
  • Viral Nonstructural Proteins / metabolism*


  • Cytokines
  • Glycoproteins
  • NF-kappa B
  • NS28 protein, rotavirus
  • Toll-Like Receptor 2
  • Toxins, Biological
  • Viral Nonstructural Proteins