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Up-Regulation of the IL-12 Receptor ß2 Chain in Crohn’s Disease¹

Tiziana Parrello^*, Giovanni Monteleone, Salvatore Cucchiara, Ivan Monteleone^*, Ladislava Sebkova^*, Patrizia Doldo^*, Francesco Luzza^* and Francesco Pallone^2,§

^* Dipartimento di Medicina Sperimentale, Università Magna Graecia di Catanzaro, Catanzaro, Italy; Department of Pediatric Gastroenterology, St. Bartholomew’s and the Royal London School of Medicine and Dentistry, London, United Kingdom; Dipartimento di Pediatria, Università di Napoli Federico II, Naples, Italy; and ^§ Dipartimento di Medicina Interna, Università di Roma tor Vergata, Rome, Italy

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-12Rß1 and IL-12Rß2. The content of IL-12Rß2, as measured at the mRNA level, is crucial in regulating Th1 differentiation. In this study we therefore investigated IL-12Rß2 RNA transcripts in CD. IL-12Rß2 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-12Rß1 transcripts were expressed at comparable levels in all samples. In CD, IL-12Rß2 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-. Transcripts for IL-12/p40 were detected in CD, HP-positive, and Salmonella colitis patients, but not in celiac disease, indicating that IL-12Rß2 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-12Rß2, suggesting that IL-12 regulates IL-12Rß2 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.

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