AIM： To investigate the influence of fish oil enriched enteral diet on intestinal tissues taken from Crohn＇s disease （CD）, ulcerative colitis （UC） and non-inflamed non-IBD control patients in vitro. METHODS： Co...AIM： To investigate the influence of fish oil enriched enteral diet on intestinal tissues taken from Crohn＇s disease （CD）, ulcerative colitis （UC） and non-inflamed non-IBD control patients in vitro. METHODS： Colonoscopic biopsies from patients with active CD （n = 4）, active UC （n = 7）, and non-inflamed non-IBD control patients （n = 4） were incubated （three dilutions of 1：20, 1：10, and 1：5） with Waymouth＇s culture medium and enteral elemental diet （EO28, SHS, Liverpool, UK） modified in the fatty acid composition with fish oil （EF） in an organ culture system for 24 h. In each experimental set-up, incubation with Waymouth＇s medium alone as control was included. Tissue viability was assessed by adding bromodeoxyuridine （BrdU） to the culture fluid and immunohistochemically staining for BrdU uptake. Cytokine ratio of IL-1ra/IL-1β （low ratio indicative of inflammation） and production of those cytokines as a percentage of medium control were assayed in the culture supernatant. RESULTS： Incubation of CD-affected tissue with EF （1：20, 1：10, and 1：5） modestly and non-significantly increased IL-1ra/IL-1β ratio as compared with medium control （CD 39.1±16.1; 26.5±7.8, 47.1±16.8 vs control 13.0±2.2）, but incubation of UC-affected tissues increased IL-1ra/IL-1β ratio significantly in all three dilutions （UC 69.1±32.2, P〈0.05; 76.1±36.4, P = 0.05; 84.5±37.3, P〈0.02; vs control 10.2±3.7）. Incubation of non-inflamed non-IBD control tissue did not increase the IL-1ra/IL-1β ratio in any dilution compared to medium control （69.3±47.0, 54.1±30.6, 79.4±34.0 vs control 76.1±37.3）. Average percentage production of IL-1β indexed against medium control was significantly less in UC after EF incubation as compared with CD （UC 24.0±4.8 vs CD 51.8±8.1; P〈0.05）. Average percentage production of IL-tra was markedly higher in UC （135.9±3.4） than that in control patients （36.5±4.3） （p〈0.0001）. CONCLUSION： IBD tissues, after incubation with elemental diet modified in its fatty acid composition with fish oil, show an increase in IL-1ra/IL-1β cytokine ratio. This effect of ω-3 fatty acid modulation is significantly more marked in UC compared with CD and is accompanied by both a reduction of IL-1β and increase of IL-1ra. The positive direct anti-inflammatory effect of elemental diet with fish oil in tissue affected with UC suggests dietary treatment of UC may be possible.展开更多
Familial acne inversa (AI) is an autoinflammatory disorder that affects hair follicles and is caused by loss-of-function mutations in y-secretase component genes.We and other researchers showed that nicastrin (NCSTN) ...Familial acne inversa (AI) is an autoinflammatory disorder that affects hair follicles and is caused by loss-of-function mutations in y-secretase component genes.We and other researchers showed that nicastrin (NCSTN) is the most frequently mutated gene in familial AI.In this study,we generated a keratin 5-Cre-driven epidermis-specific Ncstn conditional knockout mutant in mice.We determined that this mutant recapitulated the major phenotypes of AI,including hyperkeratosis of hair follicles and inflammation.In Ncstnflox/flox;K5-Cre mice,the IL-36a expression level markedly increased starting from postnatal day 0 (P0),and this increase occurred much earlier than those of TNF-α,IL-23A,IL-1 3,and TLR4.RNA-Seq analysis indicated that Sprr2d,a member of the small proline-rich protein 2 family,in the skin tissues of the Ncstnflox/flox,;K5-Cre mice was also upregulated on P0.Quantitative reverse-transcription polymerase chain reaction showed that other Sprr2 genes had a similar expression pattern.Our findings suggested that IL-36a might be a key inflammatory cytokine in the pathophysiology of AI and implicate malfunction of the skin barrier in the pathogenesis of AI.展开更多
文摘AIM： To investigate the influence of fish oil enriched enteral diet on intestinal tissues taken from Crohn＇s disease （CD）, ulcerative colitis （UC） and non-inflamed non-IBD control patients in vitro. METHODS： Colonoscopic biopsies from patients with active CD （n = 4）, active UC （n = 7）, and non-inflamed non-IBD control patients （n = 4） were incubated （three dilutions of 1：20, 1：10, and 1：5） with Waymouth＇s culture medium and enteral elemental diet （EO28, SHS, Liverpool, UK） modified in the fatty acid composition with fish oil （EF） in an organ culture system for 24 h. In each experimental set-up, incubation with Waymouth＇s medium alone as control was included. Tissue viability was assessed by adding bromodeoxyuridine （BrdU） to the culture fluid and immunohistochemically staining for BrdU uptake. Cytokine ratio of IL-1ra/IL-1β （low ratio indicative of inflammation） and production of those cytokines as a percentage of medium control were assayed in the culture supernatant. RESULTS： Incubation of CD-affected tissue with EF （1：20, 1：10, and 1：5） modestly and non-significantly increased IL-1ra/IL-1β ratio as compared with medium control （CD 39.1±16.1; 26.5±7.8, 47.1±16.8 vs control 13.0±2.2）, but incubation of UC-affected tissues increased IL-1ra/IL-1β ratio significantly in all three dilutions （UC 69.1±32.2, P〈0.05; 76.1±36.4, P = 0.05; 84.5±37.3, P〈0.02; vs control 10.2±3.7）. Incubation of non-inflamed non-IBD control tissue did not increase the IL-1ra/IL-1β ratio in any dilution compared to medium control （69.3±47.0, 54.1±30.6, 79.4±34.0 vs control 76.1±37.3）. Average percentage production of IL-1β indexed against medium control was significantly less in UC after EF incubation as compared with CD （UC 24.0±4.8 vs CD 51.8±8.1; P〈0.05）. Average percentage production of IL-tra was markedly higher in UC （135.9±3.4） than that in control patients （36.5±4.3） （p〈0.0001）. CONCLUSION： IBD tissues, after incubation with elemental diet modified in its fatty acid composition with fish oil, show an increase in IL-1ra/IL-1β cytokine ratio. This effect of ω-3 fatty acid modulation is significantly more marked in UC compared with CD and is accompanied by both a reduction of IL-1β and increase of IL-1ra. The positive direct anti-inflammatory effect of elemental diet with fish oil in tissue affected with UC suggests dietary treatment of UC may be possible.
基金This work was financially supported by the National Key Research and Development Program of China(No.2016Y FC0905100)the CAMS Innovation Fund for Medical Sciences(No.2016-I2M-1-002)+3 种基金the National Natural Science Foundation of China(NSFCNos.81788101 and 81230015)the Beijing Municipal Science and Technology Commission(No.Z151100003915078)for Xue Zhangby the National NSFC(No.31271345)for Yaping Liu.
文摘Familial acne inversa (AI) is an autoinflammatory disorder that affects hair follicles and is caused by loss-of-function mutations in y-secretase component genes.We and other researchers showed that nicastrin (NCSTN) is the most frequently mutated gene in familial AI.In this study,we generated a keratin 5-Cre-driven epidermis-specific Ncstn conditional knockout mutant in mice.We determined that this mutant recapitulated the major phenotypes of AI,including hyperkeratosis of hair follicles and inflammation.In Ncstnflox/flox;K5-Cre mice,the IL-36a expression level markedly increased starting from postnatal day 0 (P0),and this increase occurred much earlier than those of TNF-α,IL-23A,IL-1 3,and TLR4.RNA-Seq analysis indicated that Sprr2d,a member of the small proline-rich protein 2 family,in the skin tissues of the Ncstnflox/flox,;K5-Cre mice was also upregulated on P0.Quantitative reverse-transcription polymerase chain reaction showed that other Sprr2 genes had a similar expression pattern.Our findings suggested that IL-36a might be a key inflammatory cytokine in the pathophysiology of AI and implicate malfunction of the skin barrier in the pathogenesis of AI.
