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 , Luke C. Davies, Julie Hixon, Wenqeng Li, Wei Shen, Lothar Steidler, Scott K. Durum

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Abstract

Background; IBD patients with acute severe colitis face systemic anti-TNF biologic rescue therapy or colectomy, if treatment with intravenous steroids fail. 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, non-infective acute murine colitis model induced by intra-rectal instillation of 2,4,6-Trinitrobenzenesulfonic acid in SJL/J mice.


Results; IL-27 attenuates acute severe colitis through 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 pro-inflammatory 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 towards colonic innate immune responses in vivo. Mucosal delivery of IL-27 has translational potential as a novel therapeutic for IBD and is a future mucosal directed rescue therapy in acute severe inflammatory bowel disease.
Original languageEnglish
Pages (from-to)1983-1995
Number of pages12
JournalInflammatory Bowel Diseases
Volume23
Issue number11
Early online date9 Oct 2017
DOIs
Publication statusPublished - Nov 2017

Keywords

  • interleukin-27
  • cytokine
  • IBD
  • colitis

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    McLean, M. H., Andrews, C., Hanson, M. L., Baseler, W. A., Anver, M. R., Senkevitch, E., Staniszewska , A. K., 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