title: Interleukin-18 prevents apoptosis via PI3K/Akt pathway in normal human keratinocytes.
abstract: 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.
authors.affiliation: Department of Ophthalmology, Institute for Advanced Medical Sciences, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan.
authors.forename: Yuka
authors.initials: Y
authors.lastname: Hosotani
authors.forename: Shin-Ichiro
authors.initials: S
authors.lastname: Kashiwamura
authors.forename: Akiko
authors.initials: A
authors.lastname: Kimura-Shimmyo
authors.forename: Atsuo
authors.initials: A
authors.lastname: Sekiyama
authors.forename: Haruyasu
authors.initials: H
authors.lastname: Ueda
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Ikeda
authors.forename: Osamu
authors.initials: O
authors.lastname: Mimura
authors.forename: Haruki
authors.initials: H
authors.lastname: Okamura
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D002478:Cells, Cultured; D000091342:Endoplasmic Reticulum Chaperone BiP; D000078404:Epidermal Cells; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D007231:Infant, Newborn; D020382:Interleukin-18 / Q000494:pharmacology* / Q000502:physiology; D015603:Keratinocytes / Q000502:physiology*; D018832:Molecular Chaperones / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D051058:Oncogene Protein v-akt / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D010766:Phosphorylation / Q000187:drug effects; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000378:metabolism
chemical_list: D053148:Caspase 3; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; D020382:Interleukin-18; D018832:Molecular Chaperones; D016328:NF-kappa B; D051058:Oncogene Protein v-akt; D019869:Phosphatidylinositol 3-Kinases; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human