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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.

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.

SUBMITTER: McLean MH

PROVIDER: S-EPMC5796760 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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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.

McLean Mairi H MH Andrews Caroline C Hanson Miranda L ML Baseler Walter A WA Anver Miriam R MR Senkevitch Emilee E Staniszewska Aleksandra K AK Smith Christopher C Davies Luke C LC Hixon Julie J Li Wenqeng W Shen Wei W Steidler Lothar L Durum Scott K SK

Inflammatory bowel diseases 20171101 11

<h4>Background</h4>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 ...[more]

PMID: 29019857

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Project description:BackgroundWe aimed to identify the risk factors associated with colonic cytomegalovirus (CMV) infection in ulcerative colitis (UC) and to compare the clinical course between antiviral therapy-treated and -untreated groups in mucosal CMV-polymerase chain reaction (PCR) -positive cases.MethodsWe retrospectively selected 46 UC patients (>15 years old) in active phase who underwent colonoscopy with biopsy and were analyzed for CMV infection by mucosal PCR between October 2011 and December 2015 at our institution. Colonic CMV in inflamed mucosa was detected using quantitative real-time PCR. The clinical course was evaluated, including need for drug therapy/surgery or drug therapy intensification. In addition, we evaluated the clinical course between CMV-DNA- cases and CMV-DNA+ cases with low viral load.ResultsAt baseline, CMV-DNA+ patients were significantly older, had higher endoscopic scores, and required higher corticosteroid doses during the past 4 weeks than CMV-DNA- patients (p< 0.05). No significant differences were observed in disease duration, disease distribution, laboratory data, or use of other medication between CMV-DNA+ and CMV-DNA- patients. In the anti-CMV-treated group with a median (range) DNA load of 16,000 (9,000-36,400), 3patients achieved remission without additional UC therapy, 2 required additional UC therapy, and 1 required colectomy despite azathioprine and infliximab therapy. In the CMV-untreated group with a median (range) DNA load of 919 (157-5,480), all patients achieved remission with UC therapy alone. No significant difference was observed in the clinical course between CMV-DNA- cases and CMV-DNA+ cases with low viral loads.ConclusionsAging, endoscopic UC activity, and corticosteroid dose predispose to colonic CMV infection, as determined by mucosal PCR, in UC. UC treatment without anti-CMV therapy may be warranted, particularly in patients with low-load CMV-DNA. Anti-CMV therapy alone does not always achieve clinical response in UC even in cases with high-load PCR.

Project description:BackgroundColonic mucosal injuries are an important manifestation of ulcerative colitis (UC), which is related to hypoxia-induced glycolysis in colonic mucosal epithelial cells (cmECs). Panax notoginseng (PN) promotes the repair of colonic mucosal injuries by inhibiting hypoxia-induced glycolysis in cmECs; However, the mechanism by which this occurs is not completely clear. Here, we are to investigate the effects of PN on glucose metabolism in cmECs in colitis and the underlying mechanism.MethodsA model of dextran sulfate sodium-induced colitis rats was used in this research, and the severity of colitis was assessed by pathology, disease activity index (DAI), and weight changes. The content of intracellular pyruvate, intracellular lactate, adenosine triphosphate (ATP), reactive oxygen species (ROS), mitochondrial ROS (mtROS), myeloperoxidase (MPO) activity, superoxide dismutase (SOD) activity, and inflammatory cytokines was detected by assay kits. The expression levels of proteins were detected by western blotting. The expression levels of the ATP4a gene were detected by quantitative polymerase chain reaction (QT-PCR).ResultsThe colonic mucosal injuries of the colitis rats were significantly worse than those of the control group. Specifically, the hypoxia-induced glycolysis and potential of hydrogen (pH) in the colonic lumen were increased, and the expression of ATP4a was downregulated in the colitis rats. PN (1.0 g/kg) promoted the repair of colonic mucosal injuries, and reversed the pH in the colonic lumen. Further, PN increased the expression of ATP4a proteins, the content of ATP, and the SOD activity, and decreased the expression of pyruvate dehydrogenase lipoamide kinase isozyme and hypoxia-inducible factor 1-alpha proteins, the content of ROS, and MPO activity in cmECs in colitis. PN also increased the expression of ATP4a, cytochrome P450 family 21 subfamily a member 2, and hydroxy-delta-5-steroid dehydrogenase, 3 beta and steroid delta-isomerase 2 proteins in the mitochondria, and decreased the content of mtROS in cmECs.ConclusionsPN alleviated the pH in the colonic lumen and hypoxia-induced glycolysis in cmECs by reducing the hypoxia-induced glycolysis caused by the downregulation of ATP4a protein, thereby promoting the repair of colonic mucosal injuries in colitis.

Dataset Information

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.

Publications

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.

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