Rotavirus NSP4 Triggers Secretion of Proinflammatory Cytokines from Macrophages via Toll-Like Receptor 2.
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.
School of Biological Sciences.
Yi
Y
Ge
Ashley
A
Mansell
James E
JE
Ussher
Anna E S
AE
Brooks
Kristy
K
Manning
Carol J H
CJ
Wang
John A
JA
Taylor
D000818:Animals; D002460:Cell Line; D016207:Cytokines / Q000378:metabolism*; D006023:Glycoproteins / Q000378:metabolism*; D054884:Host-Pathogen Interactions; D006801:Humans; D020935:MAP Kinase Signaling System; D008264:Macrophages / Q000276:immunology* / Q000821:virology*; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D012401:Rotavirus / Q000276:immunology*; D051195:Toll-Like Receptor 2 / Q000378:metabolism*; D014118:Toxins, Biological / Q000378:metabolism*; D017361:Viral Nonstructural Proteins / Q000378:metabolism*
D016207:Cytokines; D006023:Glycoproteins; D016328:NF-kappa B; C081369:NS28 protein, rotavirus; D051195:Toll-Like Receptor 2; D014118:Toxins, Biological; D017361:Viral Nonstructural Proteins