Sotetsuflavone ameliorates Crohn's disease-like colitis by inhibiting M1 macrophage-induced intestinal barrier damage via JNK and MAPK signalling

Objectives: Intestinal inflammation and intestinal barrier dysfunction are two important pathological changes in Crohn's disease (CD). Sotetsuflavone (SF) is a natural monomeric herbal compound with anti-inflammatory and cytoprotective effects that is mostly nontoxic. The effect of SF on CD-like spontaneous colitis was investigated in this study.Methods: Il-10 /mice were used as a CD model and were administered different doses of SF. Lipopolysaccharide (LPS) plus IFN-gamma-induced macrophages (RAW264.7) and a coculture system (RAW264.7 and organoids) were used in vitro. The protective effects of SF against CD-like colitis and macrophage differentiation and the mech-anisms were evaluated.Results: SF treatment markedly improved spontaneous colitis in the CD model, as shown by the following evi-dence: reductions in the DAI, macroscopic scores (3.63 +/- 1.30), colonic tissue inflammatory scores (2 +/- 0.76) and proinflammatory factor levels and the attenuation of colon shortening (8 +/- 0.93 cm) and weight loss (1.75 +/- 1.83 g). Decreased intestinal permeability and intestinal bacterial translocation rates provided evidence of the protective effect of SF on intestinal barrier function. We also found that SF suppressed M1 macrophage-induced inflammatory responses. In the coculture system of mouse colonic organoids and RAW264.7 cells, SF signifi-cantly ameliorated M1 macrophage-induced intestinal epithelial damage. In addition, SF inhibited JNK and MAPK (p38) signalling in both Il-10 / mice and LPS plus IFN-gamma-induced macrophages (RAW264.7).Conclusions: The protective effects of SF against CD-like colitis may be achieved partially by inhibiting M1 macrophage-induced intestinal barrier damage via JNK and p38 signalling. SF may have therapeutic potential for treating CD, especially considering its safety.