Fowl adenovirus serotype 4 (FAdV-4) infection induces inflammatory responses in chicken embryonic cardiac fibroblasts via PI3K/Akt and IκBα/ NF-κB signaling pathways

Fowl adenovirus serotype 4 (FAdV-4) is the main pathogen of the acute infectious disease hepatitishydropericardium syndrome (HHS). Previous studies have focused on the mechanisms of FAdV-4 caused liver injury, while studies revealing potential mechanisms of inflammatory injury in FAdV-4-infected chicken cardiac cells remain scare. Here we found that FAdV-4 successfully infected chicken embryonic cardiac fibroblasts (CECF) cells in vitro and significantly upregulated production of inflammatory cytokines including IL-1 beta , IL-6, IL8, and TNF- alpha, suggesting induction of a strong inflammatory response. Mechanistically, FAdV-4 infection increased expression of phosphorylated Akt in a time-dependent manner, while phosphorylation of Akt and production of pro-inflammatory cytokines IL-1 beta , IL-6, IL-8, and TNF- alpha were greatly reduced in FAdV-4-infected CECF cells after treatment with LY294002, a potent inhibitor of PI3K, indicating that the inflammatory response induced by FAdV-4 infection is mediated by the PI3K/Akt signaling pathway. Furthermore, FAdV-4 infection increased expression of phosphorylated I kappa B alpha, a recognized indicator of NF- kappa B activation, and treatment with the BAY11 - 7082, a selective I kappa B alpha phosphorylation and NF- kappa B inhibitor, significantly reduced I kappa B alpha phosphorylation and inflammatory cytokines (IL-1 beta , IL-6, IL-8, and TNF- alpha) production in FAdV-4-infected CECF cells, suggesting a critical role of I kappa B alpha/NF- kappa B signaling in FAdV-4-induced inflammatory responses in CECF cells. Taken together, our results suggest that FAdV-4 infection induces inflammatory responses through activation of PI3K/Akt and I kappa B alpha/NF- kappa B signaling pathways in CECF cells. These results reveal potential mechanisms of inflammatory damage in chicken cardiac cells caused by FAdV-4 infection, which sheds new insight into clarification of the pathogenic mechanism of FAdV-4 infection and development of new strategies for HHS prevention and control.