title: Th1-mediated intestinal inflammation in Crohn's disease may be induced by activation of lamina propria lymphocytes through synergistic stimulation of interleukin-12 and interleukin-18 without T cell receptor engagement.
abstract: OBJECTIVE
  The development of T helper type 1 (Th1) CD4+ T cells in the intestinal mucosa is driven by interleukin (IL)-12 produced from activated macrophages and IL-18 produced from activated macrophages and epithelial cells. Each of these two cytokines is important for the mucosal response during intestinal inflammation, but their synergistic effect is not fully understood. To characterize the synergistic effect of IL-12 and IL-18 with respect to human intestinal inflammation, we assessed the effect of IL-12 and IL-18 on lamina propria lymphocytes from normal control subjects (LPL-NL) and patients with Crohn's disease (LPL-CD).
  
  
  METHODS
  Expression of IL-12 receptor (IL-12R) beta1, beta2, and IL-18Ralpha in LPLs was analyzed by flow cytometry. The functional activity of IL- 12 and IL-18 was assessed by the effect of recombinant IL-12 and recombinant IL-18 on interferon-gamma production, the proliferative response, and the induction of IL-2R, IL-12R, and IL-18R of LPLs.
  
  
  RESULTS
  IL-12Rbeta2 expression was significantly greater in LPL-CD compared with LPL-NL. LPL-NL demonstrated a proliferative response and a significant increase in interferon-gamma production and IL-2Ralpha expression when exposed to both IL- 12 and IL- 18, but neither IL- 12 nor IL-18 were able to induce this response on their own. However, IL-12 and IL-18 produced this response in LPL-CD when administered alone. Moreover, a more pronounced synergistic effect of IL-12 and IL-18 was observed in LPL-CD. The response normally observed after administration of IL-12 and IL-18 was significantly inhibited by anti-IL-2 and anti-IL-2Ralpha monoclonal antibody. Furthermore, IL-12 was observed to upregulate IL-18Ralpha expression in LPL-CD.
  
  
  CONCLUSIONS
  These findings suggest that a combination of IL-12 and IL-18 in the absence of T cell receptor engagement may serve as a potent regulatory factor for LPL and contribute to the maintenance and enhancement of chronic inflammation in CD.
authors.affiliation: Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Okazawa
authors.forename: Takanori
authors.initials: T
authors.lastname: Kanai
authors.forename: Mamoru
authors.initials: M
authors.lastname: Watanabe
authors.forename: Motomi
authors.initials: M
authors.lastname: Yamazaki
authors.forename: Nagamu
authors.initials: N
authors.lastname: Inoue
authors.forename: Masao
authors.initials: M
authors.lastname: Ikeda
authors.forename: Masashi
authors.initials: M
authors.lastname: Kurimoto
authors.forename: Hiromasa
authors.initials: H
authors.lastname: Ishii
authors.forename: Toshifumi
authors.initials: T
authors.lastname: Hibi
mesh_terms: D002455:Cell Division / Q000187:drug effects; D003424:Crohn Disease / Q000150:complications* / Q000503:physiopathology*; D004357:Drug Synergism; D004751:Enteritis / Q000097:blood / Q000209:etiology* / Q000473:pathology; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D018664:Interleukin-12 / Q000097:blood / Q000494:pharmacology*; D020382:Interleukin-18 / Q000097:blood / Q000494:pharmacology*; D053727:Interleukin-18 Receptor alpha Subunit; D053645:Interleukin-2 Receptor alpha Subunit; D007413:Intestinal Mucosa / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D008213:Lymphocyte Activation; D008214:Lymphocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D011948:Receptors, Antigen, T-Cell / Q000502:physiology; D018123:Receptors, Interleukin / Q000378:metabolism; D053724:Receptors, Interleukin-18; D018417:Th1 Cells / Q000502:physiology
chemical_list: C508572:IL18R1 protein, human; C508017:IL2RA protein, human; D020382:Interleukin-18; D053727:Interleukin-18 Receptor alpha Subunit; D053645:Interleukin-2 Receptor alpha Subunit; D011948:Receptors, Antigen, T-Cell; D018123:Receptors, Interleukin; D053724:Receptors, Interleukin-18; D018664:Interleukin-12; D007371:Interferon-gamma