Up-regulation of the IL-12 receptor beta 2 chain in Crohn's disease

J Immunol. 2000 Dec 15;165(12):7234-9. doi: 10.4049/jimmunol.165.12.7234.

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-12Rbeta1 and IL-12Rbeta2. The content of IL-12Rbeta2, as measured at the mRNA level, is crucial in regulating Th1 differentiation. In this study we therefore investigated IL-12Rbeta2 RNA transcripts in CD. IL-12Rbeta2 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-12Rbeta1 transcripts were expressed at comparable levels in all samples. In CD, IL-12Rbeta2 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-gamma. Transcripts for IL-12/p40 were detected in CD, HP-positive, and Salmonella colitis patients, but not in celiac disease, indicating that IL-12Rbeta2 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-12Rbeta2, suggesting that IL-12 regulates IL-12Rbeta2 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Colitis / immunology
  • Colitis / metabolism
  • Crohn Disease / immunology*
  • Crohn Disease / metabolism*
  • DNA-Binding Proteins / metabolism
  • Gastric Mucosa / immunology
  • Gastric Mucosa / metabolism
  • Gastritis / immunology
  • Gastritis / metabolism
  • Helicobacter Infections / immunology
  • Helicobacter Infections / metabolism
  • Humans
  • Interferon-gamma / biosynthesis
  • Interleukin-12 / metabolism*
  • Intestinal Mucosa / immunology
  • Intestinal Mucosa / metabolism
  • Leukocytes, Mononuclear / immunology
  • Leukocytes, Mononuclear / metabolism
  • Phosphorylation
  • RNA, Messenger / biosynthesis
  • Receptors, Interleukin / biosynthesis*
  • Receptors, Interleukin / genetics
  • Receptors, Interleukin-12
  • STAT4 Transcription Factor
  • Signal Transduction / immunology
  • Th1 Cells
  • Trans-Activators / metabolism
  • Tyrosine / metabolism
  • Up-Regulation / immunology*

Substances

  • DNA-Binding Proteins
  • RNA, Messenger
  • Receptors, Interleukin
  • Receptors, Interleukin-12
  • STAT4 Transcription Factor
  • STAT4 protein, human
  • Trans-Activators
  • Interleukin-12
  • Tyrosine
  • Interferon-gamma