Interleukin-27 Is a Potential Rescue Therapy for Acute Severe Colitis Through Interleukin-10-Dependent, T-Cell-Independent Attenuation of Colonic Mucosal Innate Immune Responses

Mairi H. McLean, Caroline Andrews, Miranda L. Hanson, Walter A. Baseler, Miriam R. Anver, Emilee Senkevitch, Aleksandra K. Staniszewska, Christopher Smith, Luke C. Davies, Julie Hixon, Wenqeng Li, Wei Shen, Lothar Steidler, Scott K. Durum

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Abstract

Background: If treatment with intravenous steroids fail, inflammatory bowel disease patients with acute severe colitis face systemic anti-tumor necrosis factor biologic rescue therapy or colectomy. Interleukin (IL)-27 is a cytokine with an immunosuppressive role in adaptive immune responses. However, the IL-27 receptor complex is also expressed on innate immune cells, and there is evidence that IL-27 can impact the function of innate cell subsets, although this particular functionality in vivo is not understood. Our aim was to define the efficacy of IL-27 in acute severe colitis and characterize novel IL-27-driven mechanisms of immunosuppression in the colonic mucosa. Methods: We assessed oral delivery of Lactococcus lactis expressing an IL-27 hyperkine on the innate immune response in vivo in a genetically intact, noninfective, acute murine colitis model induced by intrarectal instillation of 2,4,6-trinitrobenzenesulfonic acid in SJL/J mice. Results: IL-27 attenuates acute severe colitis through the reduction of colonic mucosal neutrophil infiltrate associated with a decreased CXC chemokine gradient. This suppression was T cell independent and IL-10 dependent, initially featuring enhanced mucosal IL-10. IL-27 was associated with a reduction in colonic proinflammatory cytokines and induced a multifocal, strong, positive nuclear expression of phosphorylated STAT-1 in mucosal epithelial cells. Conclusion: We have defined novel mechanisms of IL-27 immunosuppression toward colonic innate immune responses in vivo. Mucosal delivery of IL-27 has translational potential as a novel therapeutic for inflammatory bowel disease, and it is a future mucosal directed rescue therapy in acute severe inflammatory bowel disease.

Original languageEnglish
Pages (from-to)1983-1995
Number of pages13
JournalInflammatory Bowel Diseases
Volume23
Issue number11
Early online date9 Oct 2017
DOIs
Publication statusPublished - 1 Nov 2017

Keywords

  • colitis
  • cytokine
  • inflammatory bowel disease
  • interleukin-27

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    McLean, M. H., Andrews, C., Hanson, M. L., Baseler, W. A., Anver, M. R., Senkevitch, E., Staniszewska, A. K., Smith, C., Davies, L. C., Hixon, J., Li, W., Shen, W., Steidler, L., & Durum, S. K. (2017). Interleukin-27 Is a Potential Rescue Therapy for Acute Severe Colitis Through Interleukin-10-Dependent, T-Cell-Independent Attenuation of Colonic Mucosal Innate Immune Responses. Inflammatory Bowel Diseases, 23(11), 1983-1995. https://doi.org/10.1097/MIB.0000000000001274