Interleukin-18 prevents apoptosis via PI3K/Akt pathway in normal human keratinocytes.

Interleukin-18 (IL-18) is a pleiotropic cytokine expressed in both immune and non-immune cells. In the present study, we demonstrate an anti-apoptotic role of IL-18 in normal human neonatal foreskin epidermal keratinocytes (NHEK-F). Cultured NHEK-F spontaneously produced the active form of IL-18. Treatment of NHEK-F cells with anti-IL-18 receptor alpha-chain neutralizing antibody increased apoptosis and caspase-3 activity. Exogenous IL-18 augmented phosphorylation of Akt and activation of NF-kappaB. The promotion of Akt phosphorylation by IL-18 was abolished by LY294002, a PI3K inhibitor, but not SN50, an NF-kappaB inhibitor, indicating that IL-18 functions via the PI3K/Akt pathway and independently of NF-kappaB. In addition, IL-18 was found to augment expression of anti-apoptotic proteins, Bcl-2, XIAP and glucose regulated protein78/BiP, while anti-IL-18 receptor alpha-chain neutralizing antibody suppressed expression of Bcl-2, XIAP, glucose regulated protein94 and protein disulfide isomerase. Taken together, these results indicate that IL-18 plays an important role in keratinocyte survival.