Chain in Crohn's Disease 2 b Up-Regulation of the IL-12 Receptor

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-12R b 1 and IL-12R b 2. The content of IL-12R b 2, as measured at the mRNA level, is crucial in regulating Th1 differentiation. In this study we therefore investigated IL-12R b 2 RNA transcripts in CD . IL-12R b 2 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-12R b 1 transcripts were expressed at comparable levels in all samples. In CD, IL-12R b 2 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- g . Transcripts for IL-12/p40 were detected in CD, HP-positive, and Salmonella colitis patients, but not in celiac disease, indicating that IL-12R b 2 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-12R b 2, suggesting that IL-12 regulates IL-12R b 2 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 PBMC were obtained from three CD and three UC patients, and three non-IBD controls. Biopsy specimens from the distal duodenum of four patients with untreated celiac disease and four normal controls were obtained during upper gastrointestinal endoscopy. Diagnosis of celiac dis- ease was made according to the original or revised European Society for Pediatric Gastroenterology and Nutrition criteria for celiac disease (24, 25). The histopathologic diagnosis was based on typical mucosal lesions with crypt cell hyperplasia, villous atrophy, and increased number of intraepi- thelial lymphocytes. All celiac disease patients were positive for anti-endomysial and anti-gliadin Abs. Control patients were under investigation for gastrointestinal symptoms, but had normal histology and were anti-endomysial and anti-gliadin Ab negative. Additional samples were taken from the gastric antrum of three patients with documented diagnosis of Helicobacter pylori (HP)-associated gastritis and three normal controls (HP-negative subjects). Biopsy specimens were snap-frozen in liquid ni-trogen and stored at 2 80°C until used. The study was approved by the department ethical committee.