A stress-induced, superoxide-mediated caspase-1 activation pathway causes plasma IL-18 upregulation.
Psychological/physical stresses are known to cause relapses of autoimmune and inflammatory diseases. To reveal a mechanism by which noninflammatory stresses affect host defenses, responses to immobilization stress in mice were investigated, focusing on the role of a multifunctional cytokine, interleukin-18 (IL-18). In the adrenal cortex, the stress induced IL-18 precursor proteins (pro-IL-18) via adrenocorticotropic hormone (ACTH) and a superoxide-mediated caspase-1 activation pathway, resulting in conversion of pro-IL-18 to the mature form, which was released into plasma. Inhibitors of caspase-1, reactive oxygen species, and P38 mitogen-activated protein kinase (MAPK) suppressed stress-induced accumulation of plasma IL-18. These inhibitors also blocked stress-induced IL-6 expression. This, together with the observation that IL-6 was not induced in IL-18-deficient mice, showed that IL-6 induction by stress is dependent on IL-18. In stressed organisms, IL-18 may influence pathological and physiological processes. Controlling the caspase-1 activating pathway to suppress IL-18 levels may provide preventative means against stress-related disruption of host defenses.
Sekiyama
Atsuo
A
Laboratory of Host Defenses, Institute for Advanced Medical Sciences, Hyogo College of Medicine, Nishinomiya, Hyogo 663-8501, Japan. yamen@basic.med.tokushima-u.ac.jp
Ueda
Haruyasu
H
Kashiwamura
Shin-Ichiro
S
Sekiyama
Ryuji
R
Takeda
Masatoshi
M
Rokutan
Kazuhito
K
Okamura
Haruki
H
D000302:Adrenal Cortex / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D020170:Caspase 1 / Q000187:drug effects / Q000378:metabolism*; D004789:Enzyme Activation / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007150:Immunohistochemistry; D020382:Interleukin-18 / Q000097:blood*; D015850:Interleukin-6 / Q000097:blood; D008297:Male; D051379:Mice; D012149:Restraint, Physical / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D013315:Stress, Psychological / Q000503:physiopathology*; D013481:Superoxides / Q000378:metabolism*; D015854:Up-Regulation
D004791:Enzyme Inhibitors; D020382:Interleukin-18; D015850:Interleukin-6; D013481:Superoxides; D020170:Caspase 1