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Immune responses in the intestine are tightly regulated to maintain a delicate balance between cells that promote host defense and those that suppress inflammation. Disruption of this balance can lead to chronic intestinal inflammation characteristic of inflammatory bowel disorders. Although the molecular factors responsible for these disorders are not currently well-understood, four mechanisms have been proposed to explain their pathogenesis. Each of these mechanisms leads to an inappropriate or exaggerated T cell response that promotes inflammation. Crohn's disease is associated with an upregulation of IL-12 family cytokines including IL-12 and IL-23. The IL-12 cytokine family, which also includes IL-27 and IL-35, play a critical role in balancing T cell-mediated pro- and anti- inflammatory immune responses. These properties suggest that IL-12 family cytokines may play a key part in the regulation of intestinal homeostasis, and ultimately, the pathogenesis of inflammatory bowel disorders.
The IL-12 Family of Cytokines Regulates T Cell-Mediated Pro- & Anti-Inflammatory Immune Responses
Intestinal homeostasis relies on the ability of the intestinal immune system to tolerate commensal microflora, while providing protective immunity against invasive microbes. Under normal physiological conditions, gut-associated dendritic cells (DCs) preferentially induce the differentiation of regulatory T (Treg) cells that secrete immunosuppressive cytokines to prevent aberrant immune responses. Pathogenic microorganisms, or those that are typically nonpathogenic but elicit a response in genetically susceptible individuals, trigger immune cell activation and inflammation. These microbes activate DCs that promote the differentiation of naïve CD4+ T cells to a Th1, Th2, or Th17 specific lineage. T helper cells, along with macrophages and DCs, secrete pro-inflammatory cytokines aimed at eliminating the causative pathogen. Breakdown of intestinal barrier function, altered immune cell reactivity to intestinal flora, or inappropriate or exaggerated T cell responses that Treg cells fail to suppress, are mechanisms that can lead to chronic inflammation and tissue destruction characteristic of inflammatory bowel disorders such as Crohn's disease and ulcerative colitis. While ulcerative colitis has been linked with increased levels of IL-13 and an excessive Th2 response, Crohn's disease is associated with an upregulation of IL-12 family cytokines including IL-12 and IL-23, and increased Th1 and Th17 activities. IL-12 and IL-23 regulate the differentiation of Th1 and Th17 cells, and along with IL-27 and IL-35, play a crucial role in the balance of pro- and anti- inflammatory immune responses. For these reasons, they have become potential targets for inhibiting the pathogenesis of inflammatory bowel disorders.
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