Background & aims: Treatment of inflammatory bowel disease would benefit from specific targeting of therapeutics to the intestine. We developed a strategy for localized delivery of the immunosuppressive cytokine interleukin (IL)-27, which is synthesized actively in situ by the food-grade bacterium Lactococcus lactis (LL-IL-27), and tested its ability to reduce colitis in mice.
Methods: The 2 genes encoding mouse IL-27 were synthesized with optimal codon use for L lactis and joined with a linker; a signal sequence was added to allow for product secretion. The construct was introduced into L lactis. Colitis was induced via transfer of CD4(+)CD45RB(hi) T cells into Rag(-/-) mice to induce colitis; 7.5 weeks later, LL-IL-27 was administered to mice via gavage. Intestinal tissues were collected and analyzed.
Results: LL-IL-27 administration protected mice from T-cell transfer-induced enterocolitis and death. LL-IL-27 reduced disease activity scores, pathology features of large and small bowel, and levels of inflammatory cytokines in colonic tissue. LL-IL-27 also reduced the numbers of CD4(+) and IL-17(+) T cells in gut-associated lymphoid tissue. The effects of LL-IL-27 required production of IL-10 by the transferred T cells. LL-IL-27 was more effective than either LL-IL-10 or systemic administration of recombinant IL-27 in reducing colitis in mice. LL-IL-27 also reduced colitis in mice after administration of dextran sodium sulfate.
Conclusions: LL-IL-27 reduces colitis in mice by increasing the production of IL-10. Mucosal delivery of LL-IL-27 could be a more effective and safer therapy for inflammatory bowel disease.
Keywords: Crohn's Disease; DAI; DP; DSS; Ebi3; Epstein–Barr virus–induced protein 3; GI; IBD; IEL; IFN; IL; Immune Regulation; LAL; LL; LPS; Lactococcus lactis; MLN; Mouse Model; PBS; SI; T-helper cell; Th; Ulcerative Colitis; dextran sulfate sodium; disease activity index; double positive; gastrointestinal; inflammatory bowel disease; interferon; interleukin; intraepithelial lymphocyte; limulus amebocyte lysate; lipopolysaccharide; mRNA; mesenteric lymph node; messenger RNA; phosphate-buffered saline; recombinant mouse; rm; small intestine.
Published by Elsevier Inc.