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, interle...

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Published in:Immunity (Cambridge, Mass.) Mass.), 2005-06, Vol.22 (6), p.669-677
Main Authors: Sekiyama, Atsuo, Ueda, Haruyasu, Kashiwamura, Shin-ichiro, Sekiyama, Ryuji, Takeda, Masatoshi, Rokutan, Kazuhito, Okamura, Haruki
Format: Article
Language:English
Subjects:
Adrenal Cortex - drug effects
Adrenal Cortex - metabolism
Adrenal glands
Animals
Blotting, Western
Caspase 1 - drug effects
Caspase 1 - metabolism
Cytokines
Enzyme Activation - physiology
Enzyme Inhibitors - pharmacology
Immunohistochemistry
Interleukin-18 - blood
Interleukin-6 - blood
Male
Mice
Plasma
Proteins
Restraint, Physical - physiology
Signal Transduction - physiology
Stress, Psychological - physiopathology
Superoxides - metabolism
Up-Regulation
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Summary: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.
ISSN:1074-7613
1097-4180
DOI:10.1016/j.immuni.2005.04.006