Cannabinoid receptor-2 (CB2) agonist ameliorates colitis in IL-10(-/-) mice by attenuating the activation of T cells and promoting their apoptosis

Inflammatory bowel disease (IBD) is a chronic intestinal inflammation caused by hyperactivated effector immune cells that produce pro-inflammatory cytokines. Recent studies have shown that the cannabinoid system may play a critical role in mediating protection against intestinal inflammation. However, the effect of cannabinoid receptor induction after chronic colitis progression has not been investigated. Here, we investigate the effect of cannabinoid receptor-2 (CB2) agonist, JWH-133, after chronic colitis in IL-10^−/− mice. JWH-133 effectively attenuated the overall clinical score, and reversed colitis-associated pathogenesis and decrease in body weight in IL-10^−/− mice. After JWH-133 treatment, the percentage of CD4⁺ T cells, neutrophils, mast cells, natural killer (NK1.1) cells, and activated T cells declined in the intestinal lamina propria (LP) and mesenteric lymph nodes (MLN) of mice with chronic colitis. JWH-133 was also effective in ameliorating dextran sodium sulfate (DSS)-induced colitis. In this model, JWH-133 reduced the number and percentage of macrophages and IFN-γ expressing cells that were induced during colitis progression. Treatment with aminoalkylindole 6-iodo-pravadoline (AM630), a CB2 receptor antagonist, reversed the colitis protection provided by JWH-133 treatment. Also, activated T cells were found to undergo apoptosis following JWH-133 treatment both in-vivo and in-vitro. These findings suggest that JWH-133 mediates its effect through CB2 receptors, and ameliorates chronic colitis by inducing apoptosis in activated T cells, reducing the numbers of activated T cells, and suppressing induction of mast cells, NK cells, and neutrophils at sites of inflammation in the LP. These results support the idea that the CB2 receptor agonists may serve as a therapeutic modality against IBD.     

美沙拉嗪、柳氮磺胺吡啶对葡聚糖硫酸钠诱导的Balb/c小鼠急性溃疡性结肠炎的治疗和免疫影响

目的：探讨美沙拉嗪和柳氮磺胺吡啶对葡聚糖硫酸钠（DSS）致Balb/c小鼠急性溃疡性结肠炎的作用效果和对急性溃疡性结肠炎免疫功能的影响。方法：Balb/c小鼠给予3.5% DSS水溶液自由饮用7 d建立溃疡性结肠炎模型,通过测定小鼠DAI指数、脏器指数、血清IL-4、结肠组织匀浆液IL-8的表达水平和小鼠体内CD4⁺细胞、CD8⁺细胞、CD4⁺CD25⁺细胞的变化,来评价两种药物对小鼠急性溃疡性结肠炎的作用。结果：给药治疗后,美沙拉嗪组和柳氮磺胺吡啶组的DAI评分和CMDI评分均降低（P<0.01或者P<0.05）,小鼠症状缓解。结肠黏膜充血水肿减轻,且两种药物均能\\有效抑制病灶部位炎细胞的浸润。与模型组相比,美沙拉嗪组和SASP组CD3⁺细胞数增加,CD8⁺细胞数明显上升,CD4⁺CD25⁺细胞占CD4⁺细胞比例增加,血清中IL-4含量显著上升（P<0.01）,组织中IL-8含量显著下降（P<0.01）;而美沙拉嗪组CD4⁺细胞数目略有增加,SASP组CD4⁺细胞数增加比较明显。结论：美沙拉嗪和柳氮磺胺吡啶可减轻DSS诱导的UC小鼠稀便、血便症状;两种药物对UC疾病的治疗可能与提高CD4⁺细胞水平和IL-4含量及上调CD8⁺细胞水平有关。     

Chitosan oligosaccharide as potential therapy of inflammatory bowel disease: therapeutic efficacy and possible mechanisms of action

Inflammatory bowel disease (IBD) results from intestinal epithelial barrier defect and dysregulated mucosal immune response. This study aimed to evaluate the therapeutic potential of chitosan oligosaccharide (COS), a biodegradation product of dietary fiber chitosan, in the treatment of IBD and to elucidate its possible mechanisms of action. Oral administration of COS protected against mortality and intestinal inflammation in a mouse model of acute colitis induced by 5% dextran sulfate sodium (DSS). The most effective dose range of COS was 10-20 mg/kg/day. In addition, nuclear factor kappa B (NF-κB) activation, and levels of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in colonic tissues were suppressed in mice receiving COS. Similar protective effect of COS against mortality and intestinal inflammation was observed in another mouse model of acute colitis induced by rectal instillation of 4% acetic acid. Importantly, COS administration after colitis induction was effective in ameliorating intestinal inflammation in both acute colitis models induced by 5% DSS and chronic colitis models induced by cycles of 2.5% DSS. In human colonic epithelial cells (T84 cells), COS treatment prevented NF-κB activation, production of TNF-α and IL-6, and loss of epithelial barrier integrity under both lipopolysaccharide (LPS) and TNF-α-stimulated conditions. Furthermore, binding of LPS to T84 cells, and TNF-α and oxidative stress-induced apoptosis of T84 cells were prevented by treatment with COS. These results suggest that COS may be effective in the treatment of IBD through inhibition of NF-κB signaling and apoptosis of intestinal epithelial cells.     

IL-33 induces both regulatory B cells and regulatory T cells in dextran sulfate sodium-induced colitis

Interleukin (IL)-33 is a member of the IL-1 family. Serum levels of IL-33 are increased in inflammatory bowel diseases (IBD), suggesting that IL-33 is involved in the pathogenesis of IBD, although its role is not clear. In this study, we investigated the role of IL-33 in the regulation of T-helper (Th) cell and B cell responses in mesenteric lymph nodes (MLN) in mice with dextran sulfate sodium (DSS)-induced colitis. Here, we showed that IL-33-treated mice were susceptible to DSS-induced colitis as compared with PBS-treated mice. The production of spontaneous inflammatory cytokines production by macrophages or dendritic cells (DC) in MLN significantly increased, and the responses of Th2, regulatory T cells (Treg) and regulatory B cells (Breg) were markedly upregulated, while Th1 responses were significantly downregulated in MLN of IL-33-treated mice with DSS-induced colitis. Our results demonstrate that IL-33 contributes to the pathogenesis of DSS-induced colitis in mice by promoting Th2 responses, but suppressing Th1 responses, in MLN. Moreover, IL-33 treatment increased Breg and Treg responses in MLN in mice with DSS-induced colitis. Therefore, modulation of IL-33/ST2 signaling is implicated as a novel biological therapy for inflammatory diseases associated with Th1 responses.     

Matrine ameliorates spontaneously developed colitis in interleukin-10-deficient mice

Interleukin-10 (IL-10)-deficient mice spontaneously develop T cell-mediated colitis. Previous reports have shown that Matrine may reduce the symptoms of acute colitis induced by trinitrobenzene sulfonic acid (TNBS). However, whether Matrine impacts chronic colitis remains unknown. In this study, we investigated whether Matrine could limit the symptoms of spontaneously developed colitis and its potential molecular mechanisms. IL-10 deficient mice were given Matrine or a PBS control by oral gavage daily for 4 weeks and were euthanized at week 2 or week 4. We measured body weight, colon length and weight, and histological scores. We also evaluated the spontaneous secretion of IL-12/23p40, IFN-γ and IL-17 in colon explant cultures as well as IFN-γ and IL-17 secretion in unseparated mesenteric lymph node (MLN) cells, and assessed IFN-γ, IL-17, IL-1β and IL-6 mRNA expression in colon tissue. In addition, we analyzed the proportions of CD4-positive and CD8-positive cells in unseparated MLN cells. Our results show that Matrine-treated mice exhibited better body weight recovery than controls and that histological scores and spontaneously secreted IL-12/23p40, IFN-γ and IL-17 in colon tissue were significantly decreased in treated mice compared with controls. The proportion of CD4-positive cells of MLNs in treated mice was significantly smaller than that in controls at week 4. Both cytokine production and mRNA expression of IFN-γ and IL-17 were significantly reduced in treated mice compared with controls. Taken together, our results indicate that Matrine may ameliorate spontaneously developed chronic colitis and could be considered as a therapeutic alternative for chronic colitis.     

Anemoside B4 prevents acute ulcerative colitis through inhibiting of TLR4/NF-κB/MAPK signaling pathway

Anemoside B4 (B4) is a compound extracted from Pulsatilla chinensis(P. chinensis). Pharmacological studies have proved that it has certain anti-inflammatory activity. Acute ulcerative colitis (ulcerative colitis) is a non-specific inflammatory disease whose pathogenesis is not completely known, and there is no effective drugs. The purpose of this study was to investigate the protective effect of B4 on ulcerative colitis and its mechanism. In this study, the C57BL/6 mice model of ulcerative colitis was established by DSS [3% (w/v)] and treated with intraperitoneal injection of B4 and oral administration of mesalazine, respectively. During the experiment, the clinical symptoms of the mice were scored by the disease activity index (DAI). Histopathological changes were observed by HE staining. In addition, the effect of LPS on Raw264.7 cells was also studied. In vivo studies showed that B4 could prevent DSS-induced colitis mice from losing weight, shortening colon length and improving pathological changes of colon tissues. B4 significantly reduced levels of inflammatory cytokines IL-1β, IL-6, and TNF-α in colon tissues. In vitro experiments, B4 was almost nontoxic to Raw264.7 cells and could protect the Raw264.7 cells induced by LPS. In terms of mechanism, B4 significantly inhibited the activation of the TLR4 signaling pathway induced by DSS and down-regulate the expression of key proteins in the TLR4/NF-κB/MAPK signaling pathway in Raw264.7 cells induced by LPS. These findings suggest that the inhibition of B4 on ulcerative colitis may be through the TLR4/NF-κB/MAPK pathway. Therefore, B4 may be used as a potential drug for the treatment of ulcerative colitis.     

Development of non-antibiotic macrolide that corrects inflammation-driven immune dysfunction in models of inflammatory bowel diseases and arthritis

Inflammation-driven immune dysfunction supports the development of several chronic human disorders including inflammatory bowel diseases and rheumatoid arthritis. Macrolides are effective antibiotics endowed with immunomodulatory effects. In this study we report the chemical synthesis and the pharmacological characterization of CSY0073, a non-antibiotic derivative of azithromycin. CSY0073 was tested for efficacy in two experimental models of colitis induced by administering mice with dextran sulfate (DSS) and trinitrobenzene sulphonic acid (TNBS) and in collagen induced arthritis. Like azithromycin, CSY0073 improved clinical, macroscopic and histopathological scores in mice administered DSS (12.5μmol/kg/day p.o.) and TNBS (45μmol/kg/day p.o.). When administered to TNBS-treated mice, CSY0073 effectively attenuated influx of neutrophils and macrophages into the colonic mucosa and reduced the intestinal expression pro-inflammatory cytokines TNFα, IL-2 and IFNγ. CSY0073 (0.1 to 10μM) counter-regulated TNFα, IFNγ, IL-12 and IL-23 release caused by exposure of mouse spleen monocytes and CD11b+ cells isolated from the colonic lamina propria to endotoxin. CSY0073 (25μmol/kg/day) reduced clinical scores in the collagen induced murine model of rheumatoid arthritis. In myeloid cells, CSY0073 (10μM) prevented the nuclear translocation of the p65 subunit of NF-κB and its binding to canonical NF-κB responsive elements. In summary, we report a novel class of non-antibiotic 14-member macrocycles with anti-inflammatory and immune-modulatory effects. CSY0073, the prototype of this new class of macrolides exerts counter-regulatory activity on NF-κB signaling. This study suggests the exploitation of non-antibiotic macrolides in the treatment of inflammatory disorders characterized by immune dysfunction.     

Local administration of 4-Thiouridine,a novel molecule with potent anti-inflammatory properties,protects against experimental colitis and arthritis

Previous studies in a rat model of Sephadex induced lung inflammation showed that 4-Thiouridine (4SU), a thiol substituted nucleoside, was very effective in reducing edema, leukocyte influx and TNF levels in bronchoalvelolar lavage fluid. However, little is known about the factors and mechanisms underlying these effects. In the present study, we have used two separate mouse models of chronic inflammation, a model of dextran sulphate sodium (DSS) induced colitis and a model of antigen induced arthritis, to evaluate the anti-inflammatory effect of 4-thiouridine. We have analyzed a broad spectrum of inflammatory mediators in order to delineate the mechanisms behind a potential anti-inflammatory effect of 4SU. Colitis was induced in C57BL/6 mice by administration of 3.5% DSS in drinking water for 5 days and the potential anti-colitic effect of 4SU was assessed by monitoring the disease activity index (DAI), measurement of colon length and histopathological analysis of colon tissue. We analyzed tissue myeloperoxidase (MPO) activity, serum pro-inflammatory cytokines (IL-1β, IL-6 and TNF), mRNA and protein expression of pro-inflammatory cytokines, COX-2, and NF-κB activity in colitis tissue. Intracolonic administration of 4SU (5 mg/kg & 10 mg/kg.) significantly inhibited MPO activity and reduced the levels of pro-inflammatory cytokines (IL-1β, IL-6 and TNF) as well as COX-2. Further, NF-κB activation was also blocked by attenuating the phosphorylation of IkB kinase (IKK α/β) in DSS-induced colitis tissues. Arthritis was induced by intra-articular injection of mBSA in the knee of NMRI mice pre-immunized with mBSA and 4SU was administered locally by direct injection into the knee joint. The antiarthritic potential of 4SU was calculated by histopathological scores and histochemical analysis of joint tissue. Further, immunohistochemistry was used to study inflammatory cell infiltration and expression of cytokines and adhesion molecules in the synovium. Local administration of 50–100 mg/kg 4SU at the time of arthritis onset clearly prevented development of joint inflammation and efficiently inhibited synovial expression of CD18, local cytokine production and recruitment of leukocytes to the synovium. Taken together, our data clearly demonstrates a potent anti-inflammatory effect of 4SU in two experimental models. In conclusion 4SU could be a new promising candidate for therapeutic modulation of chronic inflammatory diseases like ulcerative colitis and arthritis.     

Therapeutic effects of LK 423, a phthalimido-desmuramyl-dipeptide compound, on dextran sulfate sodium-induced colitis in rodents through restoring their interleukin-10 producing capacity

A new phthalimido compound, N-[2-(2-phthalimidoethoxy)acetyl]-L-alanyl-D-glutamic acid (CAS 142489-47-2, LK 423), was examined for its possible activity to modulate levels and species of cytokines in mice carrying a specific inflamed organ. Colonic inflammation was induced in mice by giving 5% dextran sulfate sodium (DSS) solution as drinking water. The capacity of spleen cells obtained from the DSS-inflamed mice to produce interleukin-10 (IL-10) in response to mitogen was significantly reduced when compared with the capacity of spleen cells from intact mice. Treatment of the mice administered DSS by subcutaneous multiple injections with a low dose of LK423 resulted in delaying the progression to full-blown inflammation in the colon. The mitogen-stimulated spleen cells obtained from the LK423-treated mice yielded significantly greater amounts of IL-10 and IL-6 than the untreated DSS group, and the peritoneal cells from the LK423-treated mice produced significantly lower levels of tumor necrosis factor alpha (TNF alpha). Based on this prophylactic effect of LK423 in the murine colitis model, its therapeutic effect was examined in rats in which colitis had been induced by feeding 3% DSS for 12 days. Intracolonic administration of LK423 to these rats for 7 days resulted in diminishing the ulcerative area in the colon. The immunological characteristics of this new compound are discussed from the point of view of its possible application as a therapeutic agent for inflammatory bowel diseases (IBD) and other inflammatory diseases.     

PPARα contributes to colonic protection in mice with DSS-induced colitis

Inflammatory bowel disease (IBD) is characterized by repeated chronic inflammation of the gastrointestinal tract. We have used the complementary model of colonic inflammation to examine the roles of peroxisome proliferator-activated receptor α (PPARα) in colonic inflammation and thus its possible role in IBD. We characterized an innate immune-mediated model of colitis induced by dextran sulfate sodium (DSS). Mice with DSS-induced colitis were injected with Wy-14643 (2 mg/kg) as a PPARα agonist every day from day 0 to day 5. We show that mice given Wy-14643 were less susceptible to experimental acute colitis induced by DSS, and this decreased susceptibility was correlated with decreased production of IFNγ, IL-1β, IL-6, and TNF-α. Our findings suggest that PPARα has a role in controlling colonic inflammation and mucosal tissue homeostasis.     

Protect dextran sulfate sodium-induced ulcerative colitis in mice by neferine,a natural product from Nelumbo nucifera Gaertn

OBJECTIVE Ulcerative colitis(UC) is a long lasting inflammatory disease of the colon. Epidemiological studies showed that the prevalence and incidence of UC is increasing worldwide in recent years. Neferine is a natural alkaloid isolated from Nelumbo nucifera Gaertn with a variety of biological activities. This study is designed to evaluate the protective effect of neferine on dextran sulfate sodium(DSS)-induced experimental UC in mice.METHODS In this experimental study, 4% DSS was used to induced the UC mice model. Neferine(5 and10 mg · kg-1) was administrated by intraperitoneal injection(ip). The clinical symptoms and disease activity index(DAI) scores were recorded and calculated. The pathological changes of colon tissues were detected by H&E staining. The levels of inflammatory mediators were detected by ELISA kits. Western blotting and immunohistochemistry were used for protein expressions. RESULTS Neferine treatment significantly alleviated DSS-induced UC by inhibiting weight loss, decreasing DAI scores, and alleviating the pathological changes in colon tissues.Furthermore, neferine significantly decreased the serum levels of pro-inflammatory cytokines including TNF-α,IL-1β, and IL-6 and increased anti-inflammatory cytokine IL-10. The increased myeloperoxidase(MPO) activity and nitric oxide(NO) in colon tissues were also inhibited.In addition, neferine significantly down-regulated inducible nitric oxide synthase(i NOS), cyclooxygenase-2(COX-2), and intercellular cell adhesion molecule 1(ICAM-1) expression in colon tissues. CONCLUSION These results provide evidence that neferine could protect DSS-induced UC symptoms in experimental mice model.The underlying mechanisms might be through inhibition of inflammation.     

Blockade of adenosine A2B receptors ameliorates murine colitis

Background and purpose:The adenosine 2B (A(2B)) receptor is the predominant adenosine receptor expressed in the colon. Acting through the A(2B) receptor, adenosine mediates chloride secretion, as well as fibronectin and interleukin (IL)-6 synthesis and secretion in intestinal epithelial cells. A(2B) receptor mRNA and protein expression are increased during human and murine colitis. However, the effect of the A(2B) receptor in the activation of the intestinal inflammatory response is not known. In this study, we examined the effect of A(2B) receptor antagonism on murine colitis.Experimental approach:Dextran sodium sulphate (DSS)-treated mice and piroxicam-treated IL-10(-/-) mice were used as animal models of colitis. The A(2B) receptor-selective antagonist, ATL-801, was given in the diet.Key results:Mice fed ATL-801 along with DSS showed a significantly lower extent and severity of colitis than mice treated with DSS alone, as shown by reduced clinical symptoms, histological scores, IL-6 levels and proliferation indices. The administration of ATL-801 prevented weight loss, suppressed the inflammatory infiltrate into colonic mucosa and decreased epithelial hyperplasia in piroxicam-treated IL-10(-/-) mice. IL-6 and keratinocyte-derived chemokine (KC) concentrations in the supernatants of colonic organ cultures from colitic mice were significantly reduced by ATL-801 administration.Conclusions and implications:Taken together, these data demonstrate that the intestinal epithelial A(2B) receptor is an important mediator of pro-inflammatory responses in the intestine and that A(2B) receptor blockade may be an effective therapeutic strategy to treat inflammatory bowel disease.British Journal of Pharmacology (2008) 155, 127-137; doi:10.1038/bjp.2008.227; published online 9 June 2008.     

High fat diet exacerbates dextran sulfate sodium induced colitis through disturbing mucosal dendritic cell homeostasis

Epidemiological studies have shown that fat rich western diet contributes to the high incidence of inflammatory bowel disease (IBD). Moreover, accumulated data indicated that fat dietary factor might promote the change of the composition and metabolism in commensal flora. But, the exact mechanisms for fatty diet in gut inflammation are not well demonstrated. In this study, we found that high fat diet (HFD) promoted inflammation and exacerbated the disease severity of dextran sulfate sodium (DSS) induced colitis in mice. Compared with low fat diet (LFD)/DSS mice, shorter colon length, more epithelial loss and crypt destruction and more Gr-1⁺ myeloid inflammatory cells infiltration in colons were observed in HFD/DSS cohorts. Interestingly, such HFD mediated inflammation accompanied with the dys-regulation of hematopoiesis, and more hematopoiesis stem and progenitor cells were detected in colon and spleen. We further analyzed the effects of HFD and DSS treatment on mucosal DC subsets, and found that DSS treatment in LFD mice mainly dramatically increased the percentage of CD11c⁺ CD103⁻ CD11b⁺ DCs in lamina propria (LP). While, in HFD/DSS mice, HFD pre-treatment not only increased the percentage of CD11c⁺ CD103⁻ CD11b⁺ DCs, but also decreased CD11c⁺ CD103⁺ CD11b⁺ in both LP and mesenteric lymph nodes (MLN) in mice with colitis. This disequilibrium of mucosal dendritic cells in HFD/DSS mice may depend on the reduced levels of buytrate and retinoic acid. Thus, this study declared the effects of HFD on gut microenviroment, and further indicated its potential role in the development of DSS induced colitis.     

Sodium butyrate inhibits the NF-kappa B signaling pathway and histone deacetylation,and attenuates experimental colitis in an IL-10 independent manner

Butyrate is a bacterial metabolite of dietary fiber in the colon that has been used to treat inflammatory disease. However, the effect of oral supplementation with butyrate on colitis has not been fully explored. We evaluated the effects of and mechanisms underlying oral supplementation with butyrate on experimental murine colitis. In an in vitro study, we found that LPS induced the secretion of cytokines (i.e., IL-8 in COLO 205; TNF-α, IL-6, IL-12, and IL-10 in RAW 264.7; and TNF-α, IL-6 and IL-12 in peritoneal macrophages obtained from IL-10-deficient [IL-10^−/−] mice). Butyrate (100 μM and 500 μM) inhibited pro-inflammatory cytokine production (i.e., IL-8 in COLO205 and TNF-α, IL-6 and IL-12 in macrophages) but promoted anti-inflammatory cytokine (i.e., IL-10) production in RAW264.7 cells. Butyrate attenuated both the LPS-induced degradation/phosphorylation of IκBα and DNA binding of NF-κB and enhanced histone H3 acetylation. To confirm that butyrate played a protective role in colitis, an acute colitis model was induced using dextran sulfate sodium (DSS) and a chronic colitis model was induced in IL-10^−/− mice. The administration of oral butyrate (100 mg/kg) significantly improved histological scores in both colitis models, including the IL-10^−/− mice. In immunohistochemical staining, IκBα phosphorylation was attenuated, and histone H3 acetylation was reversed in the treated colons of both colitis models. Our results indicate that oral supplementation with butyrate attenuates experimental murine colitis by blocking NF-κB signaling and reverses histone acetylation. These anti-colitic effects of butyrate were IL-10-independent. Butyrate may therefore be a therapeutic agent for colitis.     

Anti-interleukin-6 therapy for Crohn's disease

Proinflammatory cytokines have been demonstrated to play a crucial role in the pathogenesis and physiopathology of various chronic inflammatory conditions including Crohn's disease (CD). Among these cytokines, interleukin-6 (IL-6) must be especially important because increased serum concentrations of acute phase proteins, reduced level of serum albumin, and remarkable thrombocytosis are all well-explained by the increased level of IL-6. Moreover, IL-6 is capable of stimulating even IL-6 receptor (IL-6R) negative cells such as vascular endothelial cells when complexed to soluble form of IL-6R (sIL-6R), and serum level of IL-6 as well as sIL-6R has been demonstrated to increase during inflammation. To investigate the therapeutic potential of IL-6 signaling blockade for CD, anti-IL-6R monoclonal antibody (mAb) was introduced to various murine models of colitis. Anti-IL-6R mAb successfully prevented wasting disease and the development of macroscopic and histological lesions. It suppressed the accumulation of ICAM-1 positive and Mac-1 positive cells in the lamina propria (LP) and the expression of ICAM-1 and VCAM-1 by vascular endothelial cells. Expansion of colonic and splenic CD4(+) T cells was reduced as well as the colonic expression of tumor necrosis factor alpha (TNF-alpha), IL-1beta, and interferon gamma (IFN-gamma) mRNA without affecting the production of transforming growth factor beta (TGF-beta), IL-10, and IL-4 mRNA. The treatment also suppressed established colitis by inducing LP T cell apoptosis. These results strongly suggest that specific targeting of IL-6/sIL-6R pathway will be a promising new approach for the treatment of CD, and the clinical trial of humanized anti-IL-6R mAb is now under way.     

Andrographolide sulfonate ameliorates chronic colitis induced by TNBS in mice via decreasing inflammation and fibrosis

Inflammatory bowel disease could result in diarrhea and abdominal pain, as well as potential complications such as tissue fibrosis. The therapeutic effect of andrographolide sulfonate on acute murine experimental colitis induced by 2, 4, 6-trinitrobenzene sulfonic acid (TNBS) has been confirmed. In the study here, chronic colitis triggered by repeated intrarectal administration of TNBS was established and the effect of andrographolide sulfonate was examined. Repeated TNBS administration induced substantial mice death, which was significantly decreased by andrographolide sulfonate treatment. The elevation of inflammatory cytokines including IL-6, IL-17A, TNF-α as well as IFN-γ in colonic tissues levels were decreased after administration of andrographolide sulfonate. Next, CD4⁺ T cell and macrophage infiltration was found to descend. The subset of pathogenic CD4⁺ T cell subset including CD4⁺IFN-γ⁺ (Th1) and CD4⁺IL-17A⁺ (Th17) were also suppressed by andrographolide sulfonate. Further, the restrain of p38 and p65 activation were also observed after andrographolide sulfonate administration. Finally, TNBS-induced colonic epithelial damage as well as fibrosis were significantly mitigated by andrographolide sulfonate. Based on the results got here, we can make a conclusion that andrographolide sulfonate could decrease inflammation and epithelial damage as well as fibrosis thus ameliorating chronic colitis in mice. Our study suggest the possible use of andrographolide sulfonate for chronic colitis treatment in clinical.     

Embelin ameliorates dextran sodium sulfate-induced colitis in mice

Embelin has been used to treat fever, inflammatory diseases, and a variety of gastrointestinal ailments for thousands of years. Although reports indicate that embelin has anti-inflammatory and anti-tumor effects, its effects on ulcerative colitis have not been previously explored. The purpose of the present work was to evaluate the anti-inflammatory effect of embelin on dextran sulfate sodium (DSS)-induced colitis. Experimental colitis was induced in BALB/c mice by dissolving 5% DSS in their drinking water for 7days. Embelin (10, 30 or 50mg/kg body weight) was administrated daily per oral route for 7days. Embelin significantly attenuated DSS-induced DAI scores and tissue MPO accumulation, which implied that it suppressed weight loss, diarrhea, gross bleeding, and the infiltrations of immune cells. Embelin administration also effectively and dose-dependently prevented shortening of colon length and enlargement of spleen size. Histological examinations indicated that embelin suppressed edema, mucosal damage, and the loss of crypts induced by DSS. Furthermore, embelin inhibited the abnormal secretions and mRNA expressions of pro-inflammatory cytokines, such as, TNF-α, IL-1β, and IL-6. These results suggest that embelin has an anti-inflammatory effect at colorectal sites that is due to the down-regulations of the productions and expressions of inflammatory mediators, and that it may have therapeutic value in the setting of inflammatory bowel disease (IBD).     

The expression of LEC/CCL16, a powerful inflammatory chemokine, is upregulated in ulcerative colitis

Ulcerative colitis (UC) is a chronic inflammatory disease of unknown aetiology and pathogenesis. The presence in the colonic mucosa of reactive cells expressing proinflammatory cytokines and chemokines is associated with high levels of IL-10, an anti-inflammatory cytokine. Our aim was to investigate the role of IL-10 and the beta chemokine LEC/CCL16 selectively up-regulated by IL-10 in inflammatory cell recruitment and cytokine and chemokine production during UC. We studied histologically, immunohistochemically and ultrastructurally colonic biopsies from 20 active UC patients and 10 control specimens taken far from any macroscopically detectable lesion in age and sex-matched patients with noninflammatory bowel disease. In active UC, immature dendritic cells (DCs) in the LP are associated with IL-10 in the T cell rich area. Furthermore, most of the LP-infiltrating macrophages strongly expressed LEC/CCL16, a chemokine upregulated by IL-10. To evaluate if LEC/CCL16 plays a role in the inflammatory reaction present in UC, we performed morphological studies in mice injected s.c. with syngeneic tumor cells engineered to produce LEC/CCL16. We found that the LEC protein locally released by LEC-gene-transfected tumor cells is a potent proinflammatory chemokine that induces the recruitment of a reactive infiltrate, and an angiogenic process mirroring that in human UC.