Submitted on December 28, 2005
Accepted on September 6, 2006
IL-18 mediates the formation of stress-induced, histamine-dependent gastric lesion
Hitomi Seino1, Haruyasu Ueda2, Masahiro Kokai3, Noriko M Tsuji4, Shin-ichiro Kashiwamura2, Yoshio Morita5, and Haruki Okamura2*
1 Department of Neuropsychiatry, Hyogo College of Medicine, Nishinomiya, Japan; Laboratory of Host Defenses, Hyogo College of Medicine, Nishinomiya, Japan
2 Laboratory of Host Defenses, Hyogo College of Medicine, Nishinomiya, Japan
3 Faculty of Humanities and Sciences, Kobe Gakuin University, Kobe, Japan
4 Age Dimension Research Center, National Institute of Advanced Industrial Science and Technology, Tsukuba, Ibaragi, Japan
5 Department of Neuropsychiatry, Hyogo College of Medicine, Nishinomiya, Japan
* To whom correspondence should be addressed. E-mail: haruoka{at}hyo-med.ac.jp.
A role of IL-18 in the induction of gastric lesions by water-immersion and restraint stress (WRS) was investigated. When wild-type BALB/c mice were exposed to WRS, levels of IL-18 in the serum and stomach increased rapidly with the development of acute gastric lesions. In IL-18-deficient mice (IL-18KO mice) similarly exposed to WRS, no gastric lesion was observed, but the administration of IL-18 before exposure to WRS resulted in the induction of WRS-induced gastric lesions. WRS enhanced gastric histidine decarboxylase (HDC) activity with concomitant increases in the gastric histamine content. In IL-18KO mice, the WRS-induced elevation of gastric HDC activity and histamine levels was much less than that in wild-type mice, but augmented by prior administration of IL-18. Treatment of wild-type mice with cimetidine, a histamine H2-receptor antagonist, inhibited the formation of WRS-induced gastric lesions with no effect on the induction of gastric IL-18 by WRS. Levels of corticosterone, one of the stress indicators, were lower in IL-18KO mice than in wild-type mice. The glucocorticoid receptor antagonist mifepristone had no effect on gastric IL-18 and histamine levels but aggravated the stress-induced gastric lesions, indicating that corticosterone was not involved in the IL-18-mediated formation of stress-induced gastric lesions. These results indicate that IL-18 is involved in the induction of gastric lesions by WRS through augmentation of HDC activity and production of histamine in the stomach.
