A role for IL-18 in human neutrophil apoptosis.
Decreased neutrophil apoptosis is associated with persistent inflammation, the severity of which correlates with serum IL-18 levels. IL-18 receptors as well as Toll-like receptors, including Toll-like receptor 4, a receptor for LPS, possess a highly conserved intracellular domain called "Toll-IL-1R domain" and activate overlapping signaling pathways. Here, we show that IL-18 modulates neutrophil apoptosis and compare its mechanism of action with LPS. We found that both IL-18 and LPS decreased neutrophil apoptosis in a similar dose- and time-dependent fashion. However, pretreatment with the phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 increased apoptosis more effectively in IL-18- than in LPS-stimulated cells, whereas the ERK inhibitor PD98059 had the same effect in both. In contrast, the p38 mitogen-activated protein kinase (MAPK) inhibitor SB203580 had no influence on apoptosis at all. Neutrophils constitutively expressed mRNA for IL-18 receptor beta, but little or no receptor alpha, both of which increased during coculture with either IL-18 or LPS in a time- and dose-dependent manner. Of the Bcl-2 family, antiapoptotic A1/Bfl-1 tended to increase on IL-18 and LPS stimulation, but was further increased despite increased apoptosis in the presence of MAPK inhibitors. Thus, human neutrophils can express mRNA for IL-18 receptors alpha and beta, and IL-18, like LPS, inhibits neutrophil apoptosis by activating PI3K and ERK pathways but not p38MAPK. However, PI3K may play more important role(s) in IL-18- than in LPS-induced inhibition of apoptosis. Mitogen-activated protein kinases seem to mediate antiapoptotic signals through factors other than Bcl-2 gene family expression.
Department of Emergency and Critical Care Medicine, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan.
Jun-ichi
J
Hirata
Joji
J
Kotani
Michiko
M
Aoyama
Shin-ichiro
S
Kashiwamura
Haruyasu
H
Ueda
Yasuhiro
Y
Kuroda
Makoto
M
Usami
Haruki
H
Okamura
Seishiro
S
Marukawa
D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D002478:Cells, Cultured; D002867:Chromones / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000502:physiology; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D020382:Interleukin-18 / Q000494:pharmacology* / Q000502:physiology; D007700:Kinetics; D008070:Lipopolysaccharides / Q000494:pharmacology; D009025:Morpholines / Q000494:pharmacology; D009504:Neutrophils / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011419:Propidium / Q000737:chemistry; D011725:Pyridines / Q000494:pharmacology; D053724:Receptors, Interleukin-18 / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology
D002867:Chromones; D048049:Extracellular Signal-Regulated MAP Kinases; D005419:Flavonoids; D007093:Imidazoles; D020382:Interleukin-18; D008070:Lipopolysaccharides; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011419:Propidium; D011725:Pyridines; D053724:Receptors, Interleukin-18; D048051:p38 Mitogen-Activated Protein Kinases; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C093642:SB 203580; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one