Cytokine-induced p38 activation feedback regulates the prolonged activation of AKT cell survival pathway initiated by reactive oxygen species in response to UV irradiation in human keratinocytes

A previous study has shown that UV activates the PI3K/AKT cell survival pat hway while inducing cell death in human skin in vivo and cultured human ker atinocytes in vitro, and yet the upstream pathway leading to the activation of AKT has not been thoroughly investigated. In this study we found that U V-induced phosphorylation of p38 and AKT in a time-dependent manner. The ph osphorylation of p38 started at 5 min post UV irradiation, peaked at about 30 min, and remained elevated up to 2 h. The phosphorylation of AKT started at 15 min post UV treatment, peaked at about 1 h, and remained elevated up to 2 h. We also found that H2O2 induced phosphorylation of p38 and AKT in a time-dependent manner. Pretreatment with NAC abolished UV-induced AKT pho sphorylation, suggesting the involvement of reactive oxygen species in AKT activation. Interestingly, SB203085, a known p38 inhibitor, had partially i nhibited UV-induced AKT phosphorylation. Further studies showed that cytoki nes such as TNF-alpha and IL-1 beta induced AKT phosphorylation in a time-d ependent manner. Pretreatment with SB203085 inhibited IL-1 beta -induced p3 8 and AKT phosphorylation. Collectively, our data suggest that UV activatio n of PI 3-kinase/AKT pathway is initiated by ROS and prolonged by feedback activation of p38 induced by released cytokines in response to UV irradiati on in cultured human keratinocytes.