title: Blockade of indoleamine 2,3-dioxygenase reduces mortality from peritonitis and sepsis in mice by regulating functions of CD11b+ peritoneal cells.
abstract: Indoleamine 2,3-dioxygenase-1 (Ido), which catalyzes the first and limiting step of tryptophan catabolism, has been implicated in immune tolerance. However, the roles of Ido in systemic bacterial infection are complicated and remain controversial. To explore this issue, we examined the roles of Ido in bacterial peritonitis and sepsis after cecal ligation and puncture (CLP) in mice by using the Ido inhibitor 1-methyl-d,l-tryptophan (1-MT), by comparing Ido(+/+) and Ido(-/-) mice, or by using chimeric mice in which Ido in the bone marrow-derived cells was deficient. Ido expression in the peritoneal CD11b(+) cells and its metabolite l-kynurenine in the serum were increased after CLP. 1-MT treatment or Ido deficiency, especially in bone marrow-derived cells, reduced mortality after CLP. Compared to Ido(+/+) mice, Ido(-/-) mice showed increased recruitment of neutrophils and mononuclear cells into the peritoneal cavity and a decreased bacterial count in the blood accompanied by increased CXCL-2 and CXCL-1 mRNA in the peritoneal cells. Ido has an inhibitory effect on LPS-induced CXCL-2 and CXCL-1 production in cultured peritoneal cells. These findings indicate that inhibition of Ido reduces mortality from peritonitis and sepsis after CLP via recruitment of neutrophils and mononuclear cells by chemokine production in peritoneal CD11b(+) cells. Thus, blockade of Ido plays a beneficial role in host protection during bacterial peritonitis and sepsis.
authors.affiliation: Faculty of Medical Science, Suzuka University of Medical Science, Suzuka, Japan Department of Informative Clinical Medicine, Gifu University Graduate School of Medicine, Gifu, Japan mhoshi@suzuka-u.ac.jp.
authors.forename: Masato
authors.initials: M
authors.lastname: Hoshi
authors.affiliation: Department of Hepatology, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan.
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Osawa
authors.affiliation: Department of Informative Clinical Medicine, Gifu University Graduate School of Medicine, Gifu, Japan.
authors.forename: Hiroyasu
authors.initials: H
authors.lastname: Ito
authors.affiliation: Department of Informative Clinical Medicine, Gifu University Graduate School of Medicine, Gifu, Japan.
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Ohtaki
authors.affiliation: Department of Informative Clinical Medicine, Gifu University Graduate School of Medicine, Gifu, Japan.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Ando
authors.affiliation: Department of Tumor Pathology, Gifu University Graduate School of Medicine, Gifu, Japan.
authors.forename: Manabu
authors.initials: M
authors.lastname: Takamatsu
authors.affiliation: Department of Tumor Pathology, Gifu University Graduate School of Medicine, Gifu, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Hara
authors.affiliation: Human Health Sciences, Kyoto University Graduate School of Medicine and Faculty of Medicine, Kyoto, Japan.
authors.forename: Kuniaki
authors.initials: K
authors.lastname: Saito
authors.affiliation: Department of Informative Clinical Medicine, Gifu University Graduate School of Medicine, Gifu, Japan.
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Seishima
mesh_terms: D000818:Animals; D001424:Bacterial Infections / Q000378:metabolism / Q000401:mortality; D039481:CD11b Antigen / Q000235:genetics / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic / Q000276:immunology*; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009504:Neutrophils / Q000378:metabolism; D010537:Peritoneum / Q000166:cytology*; D010538:Peritonitis / Q000382:microbiology* / Q000401:mortality; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018805:Sepsis / Q000382:microbiology* / Q000401:mortality
chemical_list: D039481:CD11b Antigen; C583637:IDO1 protein, mouse; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D012333:RNA, Messenger
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