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      Sustained suppression of IL-18 by employing a vaccine ameliorates intestinal inflammation in TNBS-induced murine colitis


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          To develop IL-18 peptide-based virus-like particle vaccines that elicit autoantibodies against IL-18 and to evaluate the in vivo effects of the vaccines in murine colitis.


          Recombinant IL-18 vaccines were constructed, and the effects of the vaccines were evaluated in trinitrobenzene sulfonic acid-induced acute and chronic colitis in mice.


          Two murine IL-18 peptide-based vaccines (A and D) were developed, which induced relative long-lasting specific antibodies against IL-18. Vaccine-immunized mouse antisera could partially block IL-18-induced IFN-γ production in vitro. Mice receiving vaccine D, not vaccine A, had a significant decrease in intestinal inflammation, collagen deposition and pro-inflammatory cytokine levels in colon tissue.


          IL-18 vaccine may provide a potential therapeutic approach in the treatment of Crohn’s disease.

          Lay abstract

          Many proinflammatory cytokines, including IL-18, play important roles in exaggerating the disease progression of inflammatory bowel disease (IBD). Inflammatory bowel disease is a chronic autoimmune disease, which usually requires long-term treatment. Blocking these proinflammatory cytokines by using monoclonal antibodies has shown certain clinical efficacy, but it requires repeated injection of these antibodies. To induce relative long-lasting antibodies, we developed IL-18 peptide-based virus-like particle vaccines and evaluated their therapeutic effects in a murine colitis model. Our results showed that immunization of mouse with IL-18 peptide-based vaccine could improve murine colitis, which indicated this vaccine strategy might be a potential treatment approach.

          Most cited references29

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          The NLRP3 inflammasome protects against loss of epithelial integrity and mortality during experimental colitis.

          Decreased expression of the Nlrp3 protein is associated with susceptibility to Crohn's disease. However, the role of Nlrp3 in colitis has not been characterized. Nlrp3 interacts with the adaptor protein ASC to activate caspase-1 in inflammasomes, which are protein complexes responsible for the maturation and secretion of interleukin-1beta (IL-1beta) and IL-18. Here, we showed that mice deficient for Nlrp3 or ASC and caspase-1 were highly susceptible to dextran sodium sulfate (DSS)-induced colitis. Defective inflammasome activation led to loss of epithelial integrity, resulting in systemic dispersion of commensal bacteria, massive leukocyte infiltration, and increased chemokine production in the colon. This process was a consequence of a decrease in IL-18 in mice lacking components of the Nlrp3 inflammasome, resulting in higher mortality rates. Thus, the Nlrp3 inflammasome is critically involved in the maintenance of intestinal homeostasis and protection against colitis.
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            Interleukin‐18: Biological properties and role in disease pathogenesis

            Summary Initially described as an interferon (IFN)γ‐inducing factor, interleukin (IL)‐18 is indeed involved in Th1 and NK cell activation, but also in Th2, IL‐17‐producing γδ T cells and macrophage activation. IL‐18, a member of the IL‐1 family, is similar to IL‐1β for being processed by caspase 1 to an 18 kDa‐biologically active mature form. IL‐18 binds to its specific receptor (IL‐18Rα, also known as IL‐1R7) forming a low affinity ligand chain. This is followed by recruitment of the IL‐18Rβ chain. IL‐18 then uses the same signaling pathway as IL‐1 to activate NF‐kB and induce inflammatory mediators such as adhesion molecules, chemokines and Fas ligand. IL‐18 also binds to the circulating high affinity IL‐18 binding protein (BP), such as only unbound free IL‐18 is active. IL‐18Rα may also bind IL‐37, another member of the IL‐1 family, but in association with the negative signaling chain termed IL‐1R8, which transduces an anti‐inflammatory signal. IL‐18BP also binds IL‐37 and this acts as a sink for the anti‐inflammatory properties of IL‐37. There is now ample evidence for a role of IL‐18 in various infectious, metabolic or inflammatory diseases such as influenza virus infection, atheroma, myocardial infarction, chronic obstructive pulmonary disease, or Crohn's disease. However, IL‐18 plays a very specific role in the pathogenesis of hemophagocytic syndromes (HS) also termed Macrophage Activation Syndrome. In children affected by NLRC4 gain‐of‐function mutations, IL‐18 circulates in the range of tens of nanograms/mL. HS is treated with the IL‐1 Receptor antagonist (anakinra) but also specifically with IL‐18BP. Systemic juvenile idiopathic arthritis or adult‐onset Still's disease are also characterized by high serum IL‐18 concentrations and are treated by IL‐18BP.
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              Epithelial-derived IL-18 regulates Th17 cell differentiation and Foxp3+ Treg cell function in the intestine

              Elevated levels of interleukin-18 (IL-18) are found in many chronic inflammatory disorders, including inflammatory bowel disease (IBD), and polymorphisms in the IL18R1-IL18RAP locus are associated with IBD susceptibility. IL-18 is an IL-1 family cytokine that has been proposed to promote barrier function in the intestine, but the effects of IL-18 on intestinal CD4+ T cells are poorly understood. Here, we demonstrate that IL-18R1 expression is enhanced on both effector and regulatory CD4+ T cells in the intestinal lamina propria, with Th17 cells exhibiting particularly high levels. We further show that, during steady state, intestinal epithelial cells (IEC) constitutively secrete IL-18 that acts directly on IL-18R1-expressing CD4+ T cells to limit colonic Th17 cell differentiation, in part by antagonizing IL-1R1-signalling. In addition, although IL-18R1 is not required for colonic Foxp3+ Treg cell differentiation, we found that IL-18R1 signaling was critical for Foxp3+ Treg cell mediated control of intestinal inflammation, where it promoted expression of key Treg effector molecules. Thus, IL-18 is a key epithelial-derived cytokine that differentially regulates distinct subsets of intestinal CD4+ T cells during both homeostatic and inflammatory conditions, a finding with potential implications for treatment of chronic inflammatory disorders.

                Author and article information

                Future Sci OA
                Future Sci OA
                Future Science OA
                Future Science Ltd (London, UK )
                August 2019
                30 July 2019
                : 5
                : 7
                : FSO405
                [1 ]Department of Immunology, University of Manitoba, Winnipeg R3E 3P4, Canada
                [2 ]Department of Pediatrics & Child Health, University of Manitoba, Winnipeg, R3E 3P4, Canada
                [3 ]Department of Internal Medicine, University of Manitoba, Winnipeg, R3E 3P4, Canada
                [4 ]Cellular Therapy Laboratory, CancerCare Manitoba, Winnipeg, R3A 1R9, Canada
                [5 ]Department of Pathology, University of Manitoba, Winnipeg, R3E 3P4, Canada
                Author notes
                [* ]Author for correspondence: Tel.: +1 204 787 4299; qdguan@ 123456gmail.com
                © 2019 The authors

                This work is licensed under the Creative Commons Attribution 4.0 License

                : 14 December 2018
                : 30 May 2019
                : 30 July 2019
                Page count
                Pages: 8
                Short Communication

                il-18,immunotherapy,murine colitis,peptide-based vaccine


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