title: Dietary histidine ameliorates murine colitis by inhibition of proinflammatory cytokine production from macrophages.
abstract: OBJECTIVE
  Elemental diet (ED) is effective for human Crohn's disease (CD). Although some of this effectiveness may be due to its low antigenic load and low fat content, the mechanisms remain unclear. We sought to assess the role of histidine, one of the constituent amino acids of ED, in controlling colitis.
  
  
  METHODS
  The interleukin (IL)-10-deficient (IL-10(-/-)) cell transfer model of colitis was used. SCID mice with colitis induced by transfer of IL-10(-/-) cells were maintained on experimented diets containing either single amino acids or a mixture. The severity of colitis was assessed by wet colon weight. Colonic tumor necrosis factor (TNF)-alpha messenger RNA (mRNA) expression was detected by quantitative reverse-transcription polymerase chain reaction. Mouse peritoneal macrophages were stimulated by lipopolysaccharides (LPS), with or without amino acids. The concentration of cytokines in the supernatant was determined by enzyme-linked immunosorbent assay. Inhibitor of nuclear factor (NF)-kappaB-alpha and nuclear p65 were confirmed by immunoblotting.
  
  
  RESULTS
  In the IL-10(-/-) transfer model, dietary histidine, but not alanine, reduced histologic damage and colon weight and TNF-alpha mRNA expression. Histidine inhibited LPS-induced TNF-alpha and IL-6 production by mouse macrophages in a concentration-dependent manner, whereas alanine or histidine-related metabolites had no such effect. Histidine inhibited LPS-induced NF-kappaB in macrophages.
  
  
  CONCLUSIONS
  These results showed that histidine could be a novel therapeutic agent for CD by inhibition of NF-kappaB activation, following down-regulation of proinflammatory cytokine production by macrophages. Thus, our studies provided new insights into the roles of amino acid metabolism in the pathophysiology of CD and for therapeutic strategies.
authors.affiliation: Department of Internal Medicine, School of Medicine, Keio University, Tokyo, Japan.
authors.forename: Ayatoshi
authors.initials: A
authors.lastname: Andou
authors.forename: Tadakazu
authors.initials: T
authors.lastname: Hisamatsu
authors.forename: Susumu
authors.initials: S
authors.lastname: Okamoto
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Chinen
authors.forename: Nobuhiko
authors.initials: N
authors.lastname: Kamada
authors.forename: Taku
authors.initials: T
authors.lastname: Kobayashi
authors.forename: Masaki
authors.initials: M
authors.lastname: Hashimoto
authors.forename: Tomohisa
authors.initials: T
authors.lastname: Okutsu
authors.forename: Kazutaka
authors.initials: K
authors.lastname: Shimbo
authors.forename: Tomoko
authors.initials: T
authors.lastname: Takeda
authors.forename: Hideki
authors.initials: H
authors.lastname: Matsumoto
authors.forename: Atsushi
authors.initials: A
authors.lastname: Sato
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ohtsu
authors.forename: Manabu
authors.initials: M
authors.lastname: Suzuki
authors.forename: Toshifumi
authors.initials: T
authors.lastname: Hibi
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D002908:Chronic Disease; D003092:Colitis / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control*; D019587:Dietary Supplements; D004195:Disease Models, Animal; D006639:Histidine / Q000008:administration & dosage / Q000494:pharmacology*; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D018417:Th1 Cells / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D015850:Interleukin-6; D008070:Lipopolysaccharides; D016328:NF-kappa B; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D006639:Histidine