Effect of dietary fat on intestinal inflammatory diseases.

Dietary fat has multiple roles on human health, and some dietary fat is used to treat organic diseases because of its anti-inflammatory effect. It is commonly accepted that omega-3 polyunsaturated fatty acid (PUFA) is beneficial on ischemic heart disease or rheumatic arthritis. On the contrary, effect of omega-3-PUFA on Crohn's disease remained controversial. That effect of omega-3 PUFA differs according to the location of inflamed intestine was hypothesized. To elucidate this hypothesis, to investigate the role of dietary fat on disease activity in different kind of murine models of intestinal inflammatory diseases was planned. The effect of omega-3 PUFA on small intestinal Crohn's disease model and large intestinal Crohn's disease model of mice. Chronic colitis model C57BL/6 mice received two cycles of dextran sodium sulfate solution treatment to induce chronic colitis. Feeding of omega-3 fat-rich diets exacerbated colitis with decrease in adiponectin expression. Chronic small intestinal inflammation model: SAMP1/Yit mice showed remarkable inflammation of the terminal ileum spontaneously. Feeding of omega-3 fat-rich diets for 16 weeks significantly ameliorated the inflammation of the terminal ileum. Enhanced infiltration of leukocytes and expression of mucosal addressin cell adhesion molecule-1 in intestinal mucosa was significantly decreased by omega-3 fat-rich diets treatment. Omega-3 PUFA has dual role, pro-/anti-inflammatory, on intestinal inflammatory diseases. The role of omega-3 fat and the potential for immunonutrition in inflammatory conditions of the gastrointestinal tract will be discussed.

Physiological stress exacerbates murine colitis by enhancing proinflammatory cytokine expression that is dependent on IL-18.

Psychological stress is an environmental factor considered to be a precipitating factor of inflammatory bowel disease. Interleukin (IL)-18 plays a role in stress-induced aggravation in some diseases. The aim of this study was to establish a model of murine colitis exacerbated by psychological stress and to clarify the role of IL-18 in this model. Male C57Bl/6 mice and IL-18(-/-) mice were used for this study. The mice received dextran sulfate sodium (DSS) for induction of colitis. Some mice were exposed to psychological stress using a communication box. Body weight, colonic length, and histological inflammation were measured for assessment of colitis. Tumor necrosis factor (TNF)-α and IL-18 expression in the colon and IL-18 expression in the adrenal gland were analyzed using real-time PCR. The effect of anti-IL-18 antibody was also investigated. Effects of TNF-α and IL-18 on cytokine expressions were studied using the colonic epithelial cell line LS174T. Induction of psychological stress in DSS-treated wild-type mice significantly exacerbated colitis with enhanced expression of proinflammatory cytokines and IL-18. However, induction of psychological stress in DSS-treated IL-18(-/-) mice did not aggravate colitis compared with that in the IL-18(-/-) group given only DSS treatment. Stress-induced aggravation of colitis was ameliorated significantly by anti-IL-18 antibody treatment. IL-18 did not enhance TNF-α-induced expression of intercellular adhesion molecule-1 or IL-8 in LS174T. We established a model of colitis exacerbated by psychological stress. Psychological stress enhanced IL-18 expression and plays a proinflammatory role in stress-induced aggravation of colitis.

Lemon grass (Cymbopogon citratus) ameliorates murine spontaneous ileitis by decreasing lymphocyte recruitment to the inflamed intestine.

OBJECTIVE: Aberrant leukocyte migration has been implicated in the pathogenesis of inflammatory bowel disease (IBD). Lemon grass is a natural herb that contains citral, which suppresses lymphocyte expression of gut homing molecules by inhibiting retinoic acid formation. We therefore hypothesized that lemon grass intake could ameliorate excess migration of leukocytes to the inflamed intestine in chronic ileitis. METHODS: Migration of fluorescence-labeled T cells to microvessels in the ileal mucosa of SAMP1/Yit mice was monitored using intravital microscopy. In some mice, lemon grass solution was administered for two weeks. For evaluation of the effects on chronic ileitis, mice were treated with lemon grass for 26 weeks. RESULTS: Surface expression of beta7 and CCR9 on T lymphocytes was stronger in SAMP1/Yit mice than in AKR/J mice. Lemon grass treatment attenuated the surface expression of beta7-integrin and CCR9. The number of adherent lymphocytes to microvessels in chronic inflamed ileum was significantly few when lymphocytes were isolated from lemon grass treated mice. Long-term lemon grass treatment improved ileitis in SAMP1/Yit mice, which was assessed by body weight, histological changes and the infiltration of beta7-positive cells. CONCLUSION: Lemon grass ameliorated ileitis through decreasing lymphocyte migration by inhibiting beta7-expression, suggesting its therapeutic usefulness for IBD.

Cilostazol, a specific PDE-3 inhibitor, ameliorates chronic ileitis via suppression of interaction of platelets with monocytes.

Excessive migration of monocytes to a site of intestinal inflammation contributes to tissue damage in Crohn's disease. It is known that cilostazol, a specific phosphodiesterase-3 (PDE-3) inhibitor of platelets, decreases monocyte recruitment to intestinal mucosa through suppression of platelet-monocyte interactions. The objective of this study was to clarify whether cilostazol ameliorates murine ileitis by suppression of monocyte migration. Significant inflammation was induced in the ileum of SAMP1/Yit mice at 23 wk of age after piroxicam treatment for 3 wk. Weight of the terminal ileum of mice was significantly greater with inflammatory cell infiltration in SAMP1/Yit mice than in control mice (AKR-J). Treatment of SAMP1/Yit mice with cilostazol-containing food (200 ppm) for 3 wk significantly attenuated the increase in intestinal weight and the histological changes, including invasion of F4/80-positive macrophages. A significant increase in migration of monocytes and platelets to microvessels of the ileal mucosa was observed in SAMP/Yit mice in vivo by using an intravital fluorescence microscope. Pretreatment with cilostazol significantly attenuated the increased migration of monocytes, possibly through suppression of platelet-monocyte interactions. In conclusion, a PDE-3 inhibitor ameliorates murine ileitis through attenuating migration of monocytes to the intestinal mucosa, suggesting a potential usefulness of antiplatelet drugs for treatment of Crohn's disease.

Oral tolerance induced by enterobacteria altered the process of lymphocyte recruitment to intestinal microvessels: roles of endothelial cell adhesion molecules, TGF-beta and negative regulators of TLR signaling.

OBJECTIVE: Although enterobacteria are implicated in intestinal immune response, there has been no report on how intraluminal pathogens affect lymphocyte recruitment. The aim of this study was to determine how the presence of intestinal flora affects lymphocyte migration to intestine under physiological and lipopolysaccharide (LPS)-induced inflammatory conditions. METHODS: Interaction of T-cells with ileal microvessels was monitored by using an intravital microscope in mice under germ-free (GF) and specific pathogen-free (SPF) conditions. LPS was administered into either the peritoneal cavity or duodenum before lymphocyte injection. RESULTS: Adherence of T-cells was greater in SPF than in GF mice, indicating that the presence of enterobacteria upregulated migration under physiological conditions. Intraperitoneally administered LPS significantly increased the adherence of T-cells in both GF and SPF mice accompanied by the expression of adhesion molecules and proinflammatory cytokines. However, intraluminally administered LPS did not enhance the adherence of T-cells in SPF mice. A significant induction of increase in mRNA expression of IRAK-M, a negative regulator of TLR4 signaling, and transforming growth factor beta (TGF-beta), a regulatory cytokine, was observed in SPF mice after luminal LPS treatment. CONCLUSIONS: Tolerance to intraluminally administered LPS in the lymphocyte recruitment process was induced by enterobacteria, possibly via the induction of IRAK-M and TGF-beta.

P-selectin-dependent monocyte recruitment through platelet interaction in intestinal microvessels of LPS-treated mice.

BACKGROUND: Although platelets or monocytes are thought to be involved in intestinal inflammation, there has been no report on whether platelets can modulate monocyte recruitment in intestinal microvessels. The objective of this study was to determine whether blockade of platelet adhesion attenuates monocyte recruitment in inflamed murine intestinal microvessels. METHODS: Monocytes and platelet-rich plasma were obtained from C57B6/J mice. Interaction of monocytes and platelets with intestinal microvessels was observed under an intravital microscope. Lipopolysaccharide (LPS) was administered intraperitoneally. The effects of anti-P-selectin or anti-platelets antibody treatments or phosphodiesterase (PDE) inhibitors (PDE-3 and PDE-2/4 inhibitor) treatments were also studied. RESULTS: LPS-treatment increased the rolling and adhesion of both platelets and monocytes. Pretreatment with an anti-P-selectin antibody inhibited the increased platelet adhesion to venular walls and also attenuated the monocyte adhesion. A PDE-2/4 inhibitor (ibuzilast) also ameliorated both platelet and monocyte adhesion. A PDE-3 inhibitor (cilostazol) ameliorated only monocyte adhesion without directly affecting the adhesion of platelets to microvessels. CONCLUSIONS: We observed inhibition of platelets adhesion attenuated monocytes recruitment in intestinal microvessels. Attenuation of LPS induced monocyte adhesion by a specific PDE-3 inhibitor suggests that P-selectin on activated platelets may play an important role through monocyte and platelet interaction.

Omega-3 fatty acids exacerbate DSS-induced colitis through decreased adiponectin in colonic subepithelial myofibroblasts.

BACKGROUND: Although the immunoregulatory effects of omega-3 fatty acid and adiponectin have been postulated, their role in intestinal inflammation is controversial. The aim of this study was to determine whether dietary fat intake influences activity of colonic inflammation through modulating this system. METHODS: C57BL/6 mice received dextran sulfate sodium for induction of colitis. Mice were fed a control diet, omega-3 fat-rich diet, omega-6 fat-rich diet, or saturated fat-rich diet. Some mice were administered a peroxisome proliferator activated receptor-gamma; agonist, pioglitazone. Messenger RNA expression of adiponectin and its receptors were analyzed. Adiponectin expression in colonic mucosa of ulcerative colitis patients was also analyzed. RESULTS: The receptors for adiponectin were found to be ubiquitously expressed in epithelial cells, intraepithelial lymphocytes, lamina proprial mononuclear cells, and subepithelial myofibroblasts from colonic tissue, but adiponectin was only expressed in myofibroblasts. Induction of colitis significantly decreased the expression of adiponectin in colonic mucosa. The omega-3 fat diet group, but not the other fat diet groups, showed exacerbated colitis with a further decrease of adiponectin expression. Pioglitazone treatment ameliorated the level of decrease in adiponectin expression and improved colonic inflammation induced by the omega-3 fat-rich diet. In patients with ulcerative colitis, the expression level of adiponectin in colonic mucosa was also decreased compared with that in control mucosa. CONCLUSIONS: Adiponectin was found to be expressed in myofibroblasts. Adiponectin expression was significantly suppressed by induction of colitis, and aggravation of colitis after exposure to omega-3 fat may be due to a further decrease in the expression level of adiponectin.

Blockade of PSGL-1 attenuates CD14+ monocytic cell recruitment in intestinal mucosa and ameliorates ileitis in SAMP1/Yit mice.

The pathogenesis of Crohn's disease (CD) is not known. However, monocytes and macrophages are thought to play important roles in the development of mucosal inflammation. Therefore, in this study, we examined the role of monocyte-endothelial cell interactions in senescence-accelerated mouse P1 (SAMP1)/Yit mice, a murine model of spontaneous ileitis. Fluorescence-labeled CD14+ monocytic cells isolated from the spleen and mesenteric lymph nodes of AKR/J (control) mice were injected into the tail veins of recipient (AKR/J and SAMP1/Yit) mice, and migration in the postcapillary venules (PCV) of Peyer's patches, submucosal venules, and villus microvessels of the terminal ileum was monitored by using an intravital microscope. Rolling and adhesion of CD14+ monocytic cells in the PCV of Peyer's patches and microvessels of the terminal ileum were increased in SAMP1/Yit mice. An immunohistochemical study showed increased expression of P-selectin glycoprotein-1 (PSGL-1), P-selectin, and vascular cell adhesion molecule-1 in the terminal ileum of SAMP1/Yit mice. Antibodies against these three adhesion molecules significantly inhibited adhesion of CD14+ monocytic cells to the PCV of Peyer's patches and microvessels of the terminal ileum, treatment with an anti-PSGL-1 monoclonal antibody (mAb) showing the strongest suppressive effect. Anti-PSGL-1 mAb also attenuated T cell adhesion in microvessels of intestinal mucosa. In addition, periodical administration of an anti-PSGL-1 mAb for 7 weeks significantly ameliorated ileitis of SAMP1/Yit mice. The results suggest that PSGL-1-P-selectin interaction plays an important role in monocyte-endothelial cell interactions and the development of ileitis in a murine model of CD and that the blockade of this adhesion molecule may be a novel strategy for treating CD.