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

Crohn's disease (CD) is a chronic intestinal inflammatory disorder characte rized 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 eta1 and IL-12R beta2, The content of IL-12R beta2, as measured at the mRNA level, is crucial in regulating Th1 differentiation. In this study we ther efore investigated IL-12R beta2 RNA transcripts in CD, IL-12R beta2 express ion was increased in active CD as well as Helicobacter pylori (HP)-associat ed gastritis and Salmonella colitis compared with that in inactive CD, ulce rative colitis, noninflammatory controls, and celiac disease. In contrast, IL-12R beta1 transcripts were expressed at comparable levels in all samples . In CD, IL-12R beta2 expression strictly correlated with tyrosine phosphor ylation 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 pati ents, but not in celiac disease, indicating that IL-12R beta2 up-regulation occurs only in IL-12-associated Th1 gastrointestinal diseases. Finally, we showed that stimulation of lamina propria mononuclear cells with IL-12 enh anced IL-12R beta2, suggesting that IL-12 regulates IL-12R beta2 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 di sease in CD, further supporting the view that IL-12/IL-12R signals contribu te to the inflammatory response in this condition.