8-Prenylkaempferol Suppresses Influenza A Virus-Induced RANTES Production in A549 Cells via Blocking PI3K-Mediated Transcriptional Activation of NF-κB and IRF3

Figure 8

Schematic diagram illustrating the signaling pathways involved in 8-PK's inhibition of RANTES production in H1N1-infected A549 cells. After viral ssRNA binding to TLR, the adaptor protein MyD88 couples TLR and IRAK. Subsequently, MyD88 mediates a signaling cascade in TLR-triggered cells that leads to activation of IKK-I𝜅B-NF𝜅B pathways and control inflammatory genes expression include RANTES. The core IKK complex consists of the kinases IKK𝛼 and IKK𝛽 and the regulatory IKKγ/NEMO protein. The activation of IKK𝛼/𝛽 depends on phosphorylation of serines at their activation loop. This process probably involves phosphorylation by recruit upstream kinases such as TAK1 leading to the rapid phosphorylation, ubiquitination, and ultimately proteolytic degradation of I𝜅B, which frees NF-𝜅B to translocate to the nucleus, where it regulates RANTES gene transcription. The suppression of H1N1-induced RANTES production by 8-PK may occur through downregulate I𝜅B degradation and NF-𝜅B nuclear translocation. Whether 8-PK interfere undefined upstream TAK1-IKK events to suppress RANTES production needed further study. An alternative pathway regulating RANTES production is via PI3K pathway. This leads to the activation of Akt, a cytosolic serine/threonine kinase that acts downstream of PI3K, and subsequently phosphorylation of IRF-3, a transcription factor that regulate RANTES gene expression. We found that 8-PK also can target at PI3K to block PI3K-mediated Akt phosphorylation and downregulate subsequently either NF-𝜅B nuclear translocation or IRF-3 phosphorylation in A549 cells reciprocally to suppress RANTES production. ssRNA, single strand RNA; TLR, Toll-like receptor; MyD88, myeloid differentiation (MyD) marker; IRAK, IL-1R-activated kinase; TRAF6, TNF𝛼 receptor-associated factor 6; TAK1, transforming growth factor-𝛽 (TGF-𝛽)-activated kinase 1; RANTES, regulated on activation, normal T cell expressed and secreted.