School of Biological Sciences.
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.
非结构蛋白 4（NSP4）由轮状病毒编码，具有多种与病毒发病机制相关的特性，包括肠毒性活性。最近的一项研究（O. V. Kavanagh 等人，疫苗 28:3106-3111, 2010）表明，NSP4 还具有佐剂特性，这表明它可能在轮状病毒感染的先天免疫反应中发挥作用。我们在这里报告，从轮状病毒感染的 Caco-2 细胞的培养基中纯化的 NSP4 可触发巨噬细胞样 THP-1 细胞分泌促炎细胞因子，并刺激鼠 RAW 264.7 细胞产生一氧化氮。分泌伴随着 p38 和 JNK 丝裂原激活蛋白激酶（MAPK）和核因子 NF-κB 的刺激。NSP4 可触发源自野生型而非 MyD88（-/-）或 Toll 样受体 2（TLR2（-/-））小鼠的鼠巨噬细胞分泌细胞因子，并诱导转染 TLR2 而非 TLR4 的人胚肾细胞分泌白细胞介素 8（IL-8）。我们的研究将 NSP4 鉴定为轮状病毒编码的病原体相关分子模式（PAMP），并为与人类和动物感染相关的临床症状的促炎细胞因子的产生提供了一种机制。
