Whether IL-23 plays a similar role in other models of Th1-mediated colitis, such as the TNBS-colitis, remains however unknown. the expression and functional role of IL-12 and IL-12-associated signaling pathways both in patients with CD and experimental models of colitis, thus emphasizing major differences between IL-12 and IL-23 activity on the development of intestinal inflammation. activation with anti-CD3/CD28 antibodies[1]. Therefore, the classic Th1-Th2 paradigm seems to be overly simplistic, and there is Ptgfr now sufficient evidence to believe that these two pathways can co-exist rather than being mutually exclusive in the human gut. The discovery that IFN–secreting T-LPL are abundant in CD mucosa has paved the way for studies in which the switch that controls the differentiation of such cell type was investigated. This research led to the demonstration that in CD mucosa there is increased production of IL-12, the major Th1-inducing factor in man[3,4]. IL-12 is a heterodimeric cytokine composed of two covalently linked subunits (p40 and p35) and synthesized by monocytes/macrophages/dendritic cells[5]. Transcripts for both IL-12 subunits have been detected in gastric and intestinal mucosa of patients with CD[3,6]. In addition, it was shown that lamina propria mononuclear cells isolated from intestinal mucosal areas of CD, but not UC, patients released functionally active IL-12, and that neutralization of endogenous IL-12, in CD mucosal cell cultures, resulted in a significant decrease in the number of IFN–producing cells[3,4]. IL-12 mediates its biological activities through a receptor composed of two subunits, 1 and 2[5]. Although both subunits are required to form a functional receptor, 2 appears to be crucial in controlling Forsythin Th1 cell lineage Forsythin commitment[7,8]. Consistently, high expression of IL-12R2 has been described in various Th1-mediated diseases, as well as in CD T-lamina propria lymphocytes (T-LPL)[9-11]. Additionally, CD mucosal lymphocytes express high levels of active STAT-4, a transcription factor that is activated by IL-12R signals and is necessary to promote the induction of IL-12-driven Th1-associated genes[11]. Notably, T cells from STAT-4-de?cient mice manifest impaired IFN- production in response to IL-12 and are unable to efficiently promote the development of colitis when transferred in immunode?cient mice[12]. On the other hand, studies in mice over-expressing STAT-4 revealed that such animals developed colitis that is characterized by the presence of a diffuse in?ltration of Th1 cytokine-secreting cells Forsythin in the intestinal wall[13]. While IL-12 appears to be sufficient to trigger the Th1 cell program in na?ve T cells, the expansion and maintenance of Th1 cell response in the gut would require additional signals (Figure ?(Figure1).1). Indeed, the IL-12-induced synthesis of IFN- by intestinal lamina propria T lymphocytes can be enhanced by cytokines that signal through the common -chain receptor, such as IL-7, IL-15 and IL-21[14,15]. Additionally, in CD mucosa, there is an enhanced production of biologically active IL-18, a cytokine involved in perpetuating Th1 cell responses[16,17]. Immunohistochemical analysis has localized IL-18 to both lamina propria mononuclear cells and intestinal epithelial cells. In these cells, the Forsythin expression of IL-18 is invariably associated with active subunits of IL-1-converting enzyme, a molecule capable of cleaving the precursor form of IL-18 to the active protein[16,17]. Moreover, functional studies showed that down-regulation of IL-18 expression in cultures of CD lamina propria mononuclear cells by specific IL-18 antisense oligonucleotides significantly inhibited IFN- synthesis, further supporting the concept that IL-18 serves as a strong costimulatory factor of IL-12-driven Th1 responses[16]. A newly discovered TNF-superfamily cytokine (TL1A) has also been involved in initiating or promoting the Th1 response in CD as well as in experimental models of IBD[18,19]. Another protein that could contribute to the ongoing Th1 immune response in CD is osteopontin, a 60 kDa phosphoprotein, that is highly expressed in epithelial cells and macrophages in CD and shown to increase IL-12 production in CD mucosal cells[20]. Open in a separate window Figure 1 Some putative mechanisms implicated in the induction and expansion of Th1 cells in the gut of patients with Crohns disease. Cytokines produced by antigen presenting cells, such as IL-23 and IL-12, promote the differentiation of Th1 cells. The expansion and mucosal Forsythin accumulation of this cell subtype are then sustained by additional molecules, such as IL-18, IL-7, IL-15, IL-21 and TL1A. An.