The Roles of Interleukin-17 and T Helper 17 Cells in Intestinal Barrier Function

Inflammatory Bowel Disease -Advances in Pathogenesis and Management 90 Around the same time as anti-IL-12p40 therapy was being tested, discrepancies within the T h 1/T h 2 paradigm observed over the previous two decades were beginning to be resolved Two models in particular provided the first inconsistencies with the T h 1/T h 2 hypothesis: experimental autoimmune encephalomyelitis (EAE) and collageninduced arthritis (CIA). EAE is a mouse model of human multiple sclerosis, caused by cellmediated tissue damage that results in delayed-type hypersensitivity (DTH). DTH reactions are cell-mediated immune reactions to a challenge antigen, leading to swelling, induration, and redness appearing 24 to 72 hours after antigen exposure. Initially, DTH was believed to be mediated by a T h 1 response Therefore, it was hypothesized that EAE would worsen with the addition of the T h 1 effector cytokine, IFN-. Interestingly, the results were just the opposite and IFN- administration ameliorated EAE damage Similarly, CIA as a second model of autoimmune tissue destruction was also predicted to worsen with the administration of IFN-. Although the disease did worsen when IFN- was given before the administration of the adjuvant, it was ameliorated when IFN- was given after the adjuvant (Jacob et al., 1989; These puzzling inverse relationships between disease states thought to be controlled by T h 1 responses and the presence of IFN-, eventually lead to the discovery of IL-23 and it's role as a master regulator of a new T h cell subset. IL-23, like IL-12, is a heterodimeric cytokine comprised of two subunits: a unique p19 subunit and a p40 subunit that is also shared by IL-12 (Oppmann et al., 2000). After it was discovered that IL-12 and IL-23 share a common subunit, divergent functions of these cytokines were unraveled, and the autoimmune inflammation in both EAE and CIA was found to result from the actions of IL-23, and not the T h 1 associated cytokine IL-12 (Cua et al., 2003; In the same regard, when models of innate and adaptive chronic intestinal inflammation were reevaluated, IL-23 was found to play a greater role than IL-12 in the induction of inflammation Around the time that IL-23 was found to be a central mediator of autoimmune inflammation, it was also discovered as a master regulator of an emerging T h cell subset, T h 17 This was a significant event, as it shifted the long-standing T h 1/T h 2 paradigm of inflammation to include a novel subset of adaptive T h cells. Consequently, all inflammatory conditions involving the adaptive immune response have needed re-evaluation. T h 17 cells have high expression of the transcription factors ROR and ROR-t, produce the cytokines IL-17A, IL-17F and IL-22, have high surface expression of the IL-23R as well as the chemokine receptor CCR6, and can also secrete the CCR6 ligand, CCL20 Importantly, the CCL20-CCR6 ligand-receptor pair plays an important chemoattractant role at mucosal surfaces In addition to T h 17 cells, CCR6 is also expressed on T regulatory (T reg ) cells that function to maintain homeostatic conditions By producing CCL20, T h 17 cells are able to promote the migration of additional T h 17 cells as well as T reg cells Since their characterization, T h 17 cells have been shown to play an important protective role in infectious immunity where they promote the clearance of extracellular pathogens by enhancing neutrophil recruitment and promoting the expression of antimicrobial factors. Additionally, T h 17 cells have been associated with many autoimmune diseases, such as rheumatoid arthritis, dermatitis, psoriasis, asthma, multiple sclerosis, as well as IBD Studies of human IBD have shown that the T h 17 effector cytokines IL-17A and IL-17F are both increased in the affected mucosa and sera of CD and UC patients www.intechopen.com

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