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.
Hosotani
Yuka
Y
Department of Ophthalmology, Institute for Advanced Medical Sciences, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan.
Kashiwamura
Shin-Ichiro
S
Kimura-Shimmyo
Akiko
A
Sekiyama
Atsuo
A
Ueda
Haruyasu
H
Ikeda
Tomohiro
T
Mimura
Osamu
O
Okamura
Haruki
H
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
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