T-bet upregulation and subsequent interleukin 12 stimulation are essential for induction of Th1 mediated immunopathology in Crohn's disease

Matsuoka, K.; Inoue, N.; Sato, T.; Okamoto, S.; Hisamatsu, T.; Kishi, Y.; Sakuraba, A.; Hitotsumatsu, O.; Ogata, H.; Koganei, K.; Fukushima, I.; Kanai, T.; Watanabe, M.; Ishii, H.; Hibi, T.
September 2004
Gut;Sep2004, Vol. 53 Issue 9, p1303
Academic Journal
Background and aims: Many lines of evidence suggest that T helper cell type 1 (Th1) immune responses predominate in Crohn's disease (CD). Recently, a novel transcription factor T-box expressed in T cells (T-bet) has been reported as the master regulator of Th1 development. This study was designed to investigate the role of T-bet and proinflammatory cytokines in Th1 mediated immunopathology in CD. Materials: CD4+ lamina propria mononuclear cells (LPMCs) were isolated from surgically resected specimens (CD, n = 10; ulcerative colitis (UC), n = 10; normal controls (NL), n = 5). Methods: (1) T-bet expression of CD4+ LPMCs was examined by quantitative real time polymerase chain reaction and western blotting. (2) T-bet expression of LPMCs stimulated by interleukin (IL)-12/IL-18 was analysed by western blotting. (3) Interferon γ (IFN-γ) production and T-bet expression of CD4+ peripheral blood mononuclear cells (PBMCs) were examined with or without stimulation by anti-CD3/CD28 monoclonal antibodies and/or IL-12. RESULTS: (1) T-bet expression of CD4+ LPMCs was increased in CD compared with UC and NL. (2) Synergistically, augmentation of IFN-γ production by IL-12/IL-18 was independent of T-bet expression in LPMCs. (3) T-bet was induced by T cell receptor stimulation in CD4+ PBMCs. T-bet induction correlated with IFN-γ production and with augmentation of surface expressed IL-12 receptor β2. Conclusions: T-bet induction by antigenic stimulation and subsequent stimulation by macrophage derived IL-12/IL-18 are important for establishing Th1 mediated immunopathology in CD.


Related Articles

  • Paradoxes and Pitfalls of Interleukin-33 in Atherosclerosis. Kunes, Pavel; Holubcova, Zdenka; Kolackova, Martina; Krejsek, Jan // Open Clinical Chemistry Journal;2012, Vol. 5, p13 

    Atherosclerosis is definitely considered as an inflammatory/immunopathological disease. The long-standing low-grade inflammation is focused on the components of the vessel wall. Initially, this inflammation was assumed to be driven by the pro-inflammatory Th1 cellular and cytokine immune...

  • How microorganisms tip the balance between interleukin-12 family members. Goriely, Stanislas; Neurath, Markus F.; Goldman, Michel // Nature Reviews Immunology;Jan2008, Vol. 8 Issue 1, p81 

    Interleukin-12p70 (IL-12p70) induces T-helper-1-cell responses and IL-23, a related cytokine, is the master switch in several T-cell-mediated inflammatory disorders. IL-27, another member of the IL-12 family, regulates innate and adaptive immune responses. Recently, distinct combinations of...

  • Targeting IL-12/IL-23 by Employing a p40 Peptide-Based Vaccine Ameliorates TNBS-Induced Acute and Chronic Murine Colitis. Guan, Qingdong; Ma, Yanbing; Hillman, China-Li; Qing, Gefei; Ma, Allan G.; Weiss, Carolyn R.; Zhou, Gang; Bai, Aiping; Warrington, Richard J.; Bernstein, Charles N.; Peng, Zhikang // Molecular Medicine;Jul/Aug2011, Vol. 17 Issue 7/8, p646 

    Interleukin (IL)-12 and IL-23 both share the p40 subunit and are key cytokines in the pathogenesis of Crohn's disease. Previously, we have developed and identified three mouse p40 peptide-based and virus-like particle vaccines. Here, we evaluated the effects and immune mechanisms of the optimal...

  • IL-12 p40 prevents the development of chronic enterocolitis in IL-10-deficient mice. Shiraki, Manabu; Aihara, Hiroyuki; Kinouchi, Yoshitaka; Takahashi, Seiichi; Oki, Motoji; Noguchi, Mitsunori; Takahashi, Kazuma; Miyazaki, Jun-ichi; Shimosegawa, Tooru // Laboratory Investigation (00236837);Nov2004, Vol. 84 Issue 11, p1491 

    T-helper-1 (Th1) cytokines play an important role in Crohn's disease, and interleukin-12 (IL-12), which is composed of two subunits, p40 and p35, drives Th1 differentiation. In previous reports, IL-12 p40 was shown to prevent IL-12 from binding to the receptor. We demonstrate here the effect of...

  • Interferon beta-1a for the maintenance of remission in patients with Crohn's disease: results of a phase II dose-finding study. Rossi, Claudia Pena; Hanauer, Stephen B.; Tomasevic, Ratko; Hunter, John O.; Shafran, Ira; Graffner, Hans // BMC Gastroenterology;2009, Vol. 9, Special section p1 

    Background: Crohn's disease (CD) and multiple sclerosis (MS) share common pathogenic processes. Interferon (IFN) beta-1a is effective and generally well tolerated in patients with MS and has been shown to down-regulate the expression of interleukin-12, a cytokine that is thought to be involved...

  • Diversity of Interferon γ and Granulocyte-Macrophage Colony-Stimulating Factor in Restoring Immune Dysfunction of Dendritic Cells and Macrophages During Polymicrobial Sepsis. Flohé, Stefanie B.; Agrawal, Hemant; Flohé, Sascha; Rani, Meenakshi; Bangen, Jörg M.; Schade, Ulrich F. // Molecular Medicine;May/Jun2008, Vol. 14 Issue 5/6, p247 

    The development of immunosuppression during polymicrobial sepsis is associated with the failure of dendritic cells (DC) to promote the polarization of T helper (Th) cells toward a protective Th1 type. The aim of the study was to test potential immunomodulatory approaches to restore the capacity...

  • Modulation of Cytokine Responses of Murine CD8+ a� Intestinal Intraepithelial Lymphocytes by IL-4 and IL-12. Gelfanova, Valentina; Yein-Gei Lai, Valentina; Gelfanov, Vasily; Shiey-Cheng Tzou, Vasily; Yi-Fang Tu, Vasily; Nan-Shih Liao, Vasily // Journal of Biomedical Science;1999, Vol. 6 Issue 4, p269 

    The immune responses of the intestine mucosa feature the noninflammatory type, such as IgA production and oral tolerance. Th2 type cytokines have been implicated in the induction of these noninflammatory responses. In the present study, cytokine responses of CD8+ and CD4+ TCRa�+ intestinal...

  • Interleukin-12: An Update on its Immunological Activities, Signaling and Regulation of Gene Expression. Jianguo Liu; Shanjin Cao; Sunjung Kim; Chung, Elaine Y.; Yoichiro Homma; Xiuqin Guan; Jimenez, Violeta; Xiaojing Ma // Current Immunology Reviews;2005, Vol. 1 Issue 2, p119 

    Interleukin-12 (IL-12) is a heterodimeric cytokine composed of the p35 and p40 subunits. It is produced by antigen-presenting cells and plays a critical role in host defense against intracellular microbial infection and control of malignancy via its ability to stimulate both innate and adaptive...

  • Transcription Factors Ets2 and Sp1 Act Synergistically with Histone Acetyltransferase p300 in Activating Human Interleukin-12 p40 Promoter. Hai-Jing Sun; Xin Xu; Xiu-Li Wang; Liang Wei; Fen Li; Jun Lu; Bai-Qu Huang // Acta Biochimica et Biophysica Sinica;Mar2006, Vol. 38 Issue 3, p194 

    There has been considerable interest in researching the regulatory mechanisms that control the synthesis of interleukin (IL)-12, which plays a central role in the differentiation of T-helper-1 cells. In this study, we performed a series of transient transfection experiments designed to elucidate...


Read the Article


Sign out of this library

Other Topics