Up-Regulation of the IL-12 Receptor β2 Chain in Crohn’s Disease

Abstract

Crohn’ s disease (CD) is a chronic intestinal inflammatory disorder characterized by aberrant mucosal Th1 cell activation and production of IL-12, the major Th1-driving factor. The T cell response to IL-12 is dependent on the expression of a specific receptor composed of two subunits, termed IL-12Rβ1 and IL-12Rβ2. The content of IL-12Rβ2, as measured at the mRNA level, is crucial in regulating Th1 differentiation. In this study we therefore investigated IL-12Rβ2 RNA transcripts in CD. IL-12Rβ2 expression was increased in active CD as well as Helicobacter pylori (HP)-associated gastritis and Salmonella colitis compared with that in inactive CD, ulcerative colitis, noninflammatory controls, and celiac disease. In contrast, IL-12Rβ1 transcripts were expressed at comparable levels in all samples. In CD, IL-12Rβ2 expression strictly correlated with tyrosine phosphorylation of STAT4, a key component of the IL-12-dependent Th1 polarization. This was associated with a pronounced expression of IFN-γ. Transcripts for IL-12/p40 were detected in CD, HP-positive, and Salmonella colitis patients, but not in celiac disease, indicating that IL-12Rβ2 up-regulation occurs only in IL-12-associated Th1 gastrointestinal diseases. Finally, we showed that stimulation of lamina propria mononuclear cells with IL-12 enhanced IL-12Rβ2, suggesting that IL-12 regulates IL-12Rβ2 expression in human gastrointestinal mucosa. The data show that the signaling pathway used by IL-12 to induce Th1 differentiation is increased at the site of disease in CD, further supporting the view that IL-12/IL-12R signals contribute to the inflammatory response in this condition.

Negative Regulation of Interleukin-12 Signaling by Suppressor of Cytokine Signaling-1

“…The deleterious effects of continued IL-12 signaling are evident in inflammatory disorders such as Crohn's disease (45). Therefore uncontrolled responses to IL-12 may contribute to the severe inflammatory disease in SOCS-1 Ϫ/Ϫ mice.…”

Targeting IL-12/IL-23 by Employing a p40 Peptide-Based Vaccine Ameliorates TNBS-Induced Acute and Chronic Murine Colitis

“…In active Crohn's disease, the expression of IL-12 receptors on mucosal cells is increased (5). Various immunohistological studies indicate that in situ IL-12 is overproduced by macrophages in Crohn's disease, and that macrophages isolated from the inflammatory lesions of patients with Crohn's disease produce increased amounts of IL-12 ex vivo (6).…”

“…Qingdong Guan, 1,2 Yanbing Ma, 2 China-Li Hillman, 2 Gefei Qing, 3 Allan G Ma, 1,2 Carolyn R Weiss, 1,2 Gang Zhou, 2 Aiping Bai, 2 Richard J Warrington, 4 Charles N Bernstein, 4,5 and Zhikang Peng with the downregulation of a broad array of inflammatory cytokines and chemokines in the colon (14). Recently, a genome-wide association study has reported IL-23R as an IBD gene that is highly associated with Crohn's disease (15).…”

TheHelicobacter pyloriBlood Group Antigen-Binding Adhesin Facilitates Bacterial Colonization and Augments a Nonspecific Immune Response

“…The IL-12R ␤2 chain has been shown to be selectively expressed on Th1 cells, whereas the ␤1 chain is present on both Th1 and Th2 cells (35,36). Expression of IL12R ␤2 is up-regulated in diseases characterized by a Th1-skewed immune status (37,38). Cytokines that further characterize a Th1-driven immune response are IFN-␥ and TNF-␣.…”