Background: T-cells are a main target for antiinflammatory drugs in inflammatory bowel disease. As the innate immune system is also implicated in the pathogenesis of these diseases, T-cell suppressors may not only inhibit T-cell-dependent production of proinflammatory mediators but also affect innate immune cell function. Specifically, these drugs may impair innate immune cell recruitment and activation through inhibition of T-cells or act independent of T-cell modulation. We explored the extent of immune modulation by the T-cell inhibitor tacrolimus in a murine colitis model. Methods: We assessed the effects of tacrolimus on trinitro-benzene sulphonic acid (TNBS) colitis in wildtype and Rag2-deficient mice. The severity of colitis was assessed by means of histological scores and weight loss. We further characterized the inflammation using immunohistochemistry and by analysis of isolated intestinal leukocytes at various stages of disease. Results: Tacrolimus-treated wildtype mice were less sensitive to colitis and had fewer activated T-cells. Inhibition of T-cell function was associated with strongly diminished recruitment of infiltrating neutrophils in the colon at the early stages of this model. In agreement, immunohistochemistry demonstrated that tacrolimus inhibited production of the neutrophil chemoattractants CXCL1 and CXCL2. Rag2-deficient mice displayed an enhanced baseline level of lamina propria neutrophils that was moderately increased in TNBS colitis and remained unaffected by tacrolimus. Conclusions: Both the innate and the adaptive mucosal immune system contribute to TNBS colitis. Tacrolimus suppresses colitis directly through inhibition of T-cell activation and by suppression of T-cell-mediated recruitment of neutrophils.

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Keywords CXCL1 chemokine, CXCL2 chemokine, Crohn disease, Innate immune system, Neutrophils, RAG2 protein, RNA isolation, T lymphocyte activation, T-cell, TNBS colitis, adaptive immunity, animal cell, animal experiment, animal model, animal tissue, antiinflammatory activity, article, controlled study, cytokine production, disease severity, human, human cell, immunohistochemistry, immunomodulation, immunoregulation, innate immunity, intestine cell, lamina propria, male, mouse, neutrophil chemotaxis, nonhuman, priority journal, real time polymerase chain reaction, reverse transcription polymerase chain reaction, tacrolimus, trinitrobenzenesulfonic acid, weight reduction
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van Lierop, P.P.E., de Haar, C., Lindenbergh-Kortleve, D.J., Simons-Oosterhuis, Y., van Rijt, L.S., Lambrecht, B.N.M., … Nieuwenhuis, E.E.S.. (2010). T-cell regulation of neutrophil infiltrate at the early stages of a murine colitis model. Inflammatory Bowel Diseases, 16(3), 442–451. doi:10.1002/ibd.21073