Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0009319 (colitis)
 19,384 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

TH17 is a newly identified pathogenic memory CD4 T-cell lineage with potent agonist effects in some murine experimental autoimmunity models, however, its role in tumor immunology is still unclear. Clinical experience with interleukin (IL)-2 and ipilumumab [anti-cytotoxic T-lymphocyte antigen 4 (CTLA4) antibody], particularly in treating immunogenic malignancies such as melanoma and renal cell carcinoma (RCC), has suggested an association between a variety of autoimmune phenomena and tumor regression. To investigate this issue in patients with RCC, we isolated T-cell clones from peripheral blood that released IL-17 on stimulation with their autologous RCC tumor line. Clones were generated from 1 patient before any systemic treatment by in vitro stimulation with dendritic cells, autologous tumor, and IL-2 in the presence of anti-CTLA4 antibody. That patient subsequently received treatment with ipilimumab and showed both objective tumor regression and immune-mediated colitis. Limiting dilution cloning of his tumor-dendritic cell-stimulated T cells produced the 3G8D CD4+ clone, which secreted both IL-17 and interferon-gamma when cocultured with the autologous RCC line (transduced with class II transactivation molecule to induce major histocompatibility complex-class II expression). Broader analysis of its cytokine secretion profile showed large amounts of IL-8 when cocultured with RCC, but not when triggered with phorbol 12-myristate 13-acetate and ionomycin. This led to the discovery that IL-8 was being produced by the RCC cells in response to T-cell-derived IL-17. This effect of exogenous IL-17 on IL-8 release from tumor was seen in 5 of 8 RCCs, but not in other tumors tested. Preliminary data on the frequency of IL-17-secreting T cells in the lymphocytes infiltrating RCCs suggest that there may be a positive correlation between this frequency and IL-8 production by nonlymphoid cells as determined by quantitative reverse transcription-polymerase chain reaction. This report extends the known bidirectional interactions between immune cells and malignant cells in the tumor microenvironment that can shape and modulate the host immune response to cancer.
 ...
PMID:IL-17 secreted by tumor reactive T cells induces IL-8 release by human renal cancer cells. 1923 9

A regulated low level of nitric oxide (NO) production in the body is essential for maintaining homeostasis (neuroprotection, vasorelaxation, etc.), though certain pathophysiological conditions associated with inflammation involve de novo synthesis of inducible NO synthase (iNOS) in immune cells, including macrophages. A large body of evidence indicates that many inflammatory diseases, such as colitis and gastritis, as well as many types of cancer, occur through sustained and elevated activation of this particular enzyme. The biochemical process of iNOS protein expression is tightly regulated and complex, in which the endotoxin lipopolysaccharide selectively binds to toll-like receptor 4 and thereby activates its adaptor protein MyD88, which in turn targets downstream proteins such as IRAK and TRAF6. This leads to functional activation of key protein kinases, including IkB kinases and mitogen-activated protein kinases (MAPKs), such as p38 MAPK, JNK1/2, and ERK1/2, all of which are involved in activating key transcription factors, including nuclear factor-kappaB and activator protein-1. In addition, the production of proinflammatory cytokines such as interferon-gamma and interleukin-12 potentiates iNOS induction in autocrine fashions. Meanwhile, an LPS-stimulated p38 MAPK pathway plays a pivotal role in the stabilization of iNOS mRNA, which has the AU-rich element in its 3'-untranslated region, for rapid NO production. Thus, suppression and/or inhibition of the above-mentioned signaling molecules may have a great potential for the prevention and treatment of inflammation-associated carcinogenesis. In fact, there have been numerous reports of phytochemicals found capable of targeting NO production by unique mechanisms, including polyphenols, terpenoids, and others. This review article briefly highlights the molecular mechanisms underlying endotoxin-induced iNOS expression in macrophages, and also focuses on promising natural agents that may be useful for anti-inflammation and anticarcinogenesis strategies.
 ...
PMID:Chemoprevention with phytochemicals targeting inducible nitric oxide synthase. 1936 23

Inflammatory bowel disease (IBD) is chronic inflammatory and relapsing disease of the gut. It has been known that activation of nuclear factor-kappaB (NF-kappaB) and production of proinflammatory cytokines play important roles in the pathogenesis of IBD. In this study, the effect of vanillin (4-hydroxy-3-methoxybenzaldehyde), a potent nuclear factor-kappaB (NF-kappaB) inhibitor, was evaluated in mice with trinitrobenzene sulfonic acid (TNBS)-induced colitis. Oral administration of vanillin improved macroscopic and histological features of TNBS-induced colitis in a dose-dependent manner. Vanillin not only prevented TNBS-induced colitis but also ameliorated the established colitis. By in vivo NF-kappaB bioluminescence imaging, electrophoretic mobility shift assay, and Western blot, we found that vanillin suppressed in vivo NF-kappaB activities through the inhibition of p65 translocation, inhibitor of nuclear factor-kappaB(IkappaB)-alpha phosphorylation, and IkappaB kinase activation. Furthermore, vanillin reduced the expressions of proinflammatory cytokines [interleukin (IL)-1beta, IL-6, interferon-gamma, and tumor necrosis factor-alpha] and stimulated the expression of anti-inflammatory cytokine (IL-4) in colonic tissues. In conclusion, this work identified vanillin as an anti-inflammatory compound with the capacity to prevent and ameliorate TNBS-induced colitis. Due to its safety, vanillin could be a potent candidate for the treatment of IBD.
 ...
PMID:Vanillin improves and prevents trinitrobenzene sulfonic acid-induced colitis in mice. 1942 42

Astragalus membranaceus is a medicinal herb with potential immunomodulatory property, which has been used in treating colitis-related diarrhea. In the present investigation, we aimed to further explore its anti-inflammatory activity by studying the immunoregulatory mechanism of Astragalus root extract (Am) through different routes of administration in hapten-induced colitis. 2,4-Dinitrobenzene sulfonic acid (DNBS) was used to induce experimental colitis in Sprague-Dawley rats. Results have indicated that both oral and intracolonic Am treatments (administered twice daily for three consecutive days following colitis induction) exhibited significant protection against DNBS-induced colitis in rats, indicated by decreased colonic lesion area and histological damage score as well as amelioration of the elevated colonic myeloperoxidase activity. Western immunoblotting has revealed that oral Am could diminish the overexpression of tumor necrosis factor (TNF)-alpha and interleukin (IL)-1beta, while concomitantly abolishing the inhibition of IL-10 expression in rats' colon under colitis condition. On the other hand, intracolonic Am could only reduce TNF-alpha and interferon-gamma overexpression. In summary, we have demonstrated that both oral and locally administered Am possess protective effects against experimental colitis through differential modulation of colonic cytokines. This study provides important new insights that may contribute to further development of Am as a novel therapeutic agent for treating colitis diseases.
 ...
PMID:The protective action of radix Astragalus membranaceus against hapten-induced colitis through modulation of cytokines. 1953 95

Inflammatory bowel diseases (IBD) are chronic inflammatory and relapsing diseases of the gut that may manifest as either Crohn's disease (CD) or ulcerative colitis (UC). CD and UC are immunologically different diseases characterized by exacerbated Th1 and Th2 response. T-cell resistance against apoptosis contributes to inappropriate T-cell accumulation and the perpetuation of chronic mucosal inflammation. In the present study we have investigated the effect exerted by guggulsterone (GS) a plant derived steroid isolated from the gum resin of the Commiphora mukul tree, in two models of intestinal inflammation induced in mice by trinitro-benzene sulfonic acid (TNBS) and oxazolone. We provided evidence that E-GS protects mice against development of sign and symptoms of colon inflammation. E-GS effectively attenuated the severity of wasting disease and the fecal score and colon inflammation as assessed by measuring the macroscopic- and microscopic-damage scores. Administration Z-GS failed to ameliorate colon inflammation in TNBS-induced colitis and had a partial effect in oxazolone-induced colitis. In vitro, mechanistic studies carried out using CD4+ cells isolated from the intestinal lamina propria demonstrate that GS effectively regulates the function of effector T cells by modulating cell signaling activation pathway caused by CD3/CD28. The net biological effects resulting from exposure to GS includes attenuation of generation of interleukin-2 and -4 and interferon-gamma as well as T cell proliferation. In conclusion, GS is an anti-inflammatory compound with the capacity to prevent and ameliorate T-cell-induced colitis. These data ground the use of GS, a natural cholesterol-lowering agent, in the treatment of chronic inflammatory diseases.
 ...
PMID:The plant sterol guggulsterone attenuates inflammation and immune dysfunction in murine models of inflammatory bowel disease. 1955 71

Carcinoembryonic antigen-related cellular adhesion molecule 1 (CEACAM1) is a CEA family member that has been reported to have an important role in the regulation of Th1-mediated colitis. In this study, we examined the role of CEACAM1 in an animal model of multiple sclerosis, experimental autoimmune encephalomyelitis (EAE). Treatment of C57BL/6J mice with CEACAM1-Fc fusion protein, a homophilic ligand of CEACAM1, inhibited the severity of EAE and reduced myelin oligodendrocyte glycoprotein-derived peptide (MOG(35-55))-reactive interferon-gamma and interleukin-17 production. In contrast, treatment of these animals with AgB10, an anti-mouse CEACAM1 blocking monoclonal antibody, generated increased severity of EAE in association with increased MOG(35-55)-specific induction of both interferon-gamma and interleukin-17. These results indicated that the signal elicited through CEACAM1 ameliorated EAE disease severity. Furthermore, we found that there was both a rapid and enhanced expression of CEACAM1 on invariant natural killer T cells after activation. The effect of CEACAM1-Fc fusion protein and anti-CEACAM1 mAb on both EAE and MOG(35-55)-reactive cytokine responses were abolished in invariant natural killer T cell-deficient Jalpha18(-/-) mice. Taken together, the ligation of CEACAM1 negatively regulates the severity of EAE by reducing MOG(35-55)-specific induction of both interferon-gamma and interleukin-17 via invariant natural killer T cell-dependent mechanisms.
 ...
PMID:Carcinoembryonic antigen-related cell adhesion molecule 1 modulates experimental autoimmune encephalomyelitis via an iNKT cell-dependent mechanism. 1970 Jul 60

We previously demonstrated orally administered bovine lactoperoxidase (LPO) ameliorated dextran sulfate sodium-induced colitis in mice. Here, we examine the mechanism of action of LPO. Three days after colitis induction, expression of interferon-gamma mRNA in colonic tissue was significantly decreased in mice administered LPO; while mRNA expression of interleukin (IL)-10 and regulatory T cell (Treg) marker, Foxp3, were significantly increased. The proportion of CD4+CD25+ Tregs in peripheral CD4+ T cells was also significantly elevated when LPO was administered. Nine days after colitis induction, the severity of colitis symptoms, including body weight loss and colon shortening, was reduced and expression of IL-10 mRNA was increased in mice administered LPO. The proportion of CD4+CD25+ Tregs in peripheral leukocytes was also significantly elevated when LPO was administered. These results suggest LPO ameliorates colitis by up-regulating colonic anti-inflammatory cytokines and maintaining peripheral regulatory T cells.
 ...
PMID:Orally administered lactoperoxidase ameliorates dextran sulfate sodium-induced colitis in mice by up-regulating colonic interleukin-10 and maintaining peripheral regulatory T cells. 1972 94

The critical role of phosphoinositide 3-kinase gamma (PI3Kgamma) in inflammatory cell activation and recruitment makes it an attractive target for immunomodulatory therapy. 5-Quinoxilin-6-methylene-1,3-thiazolidine-2,4-dione (AS605240), a potent PI3Kgamma inhibitor, has been reported to ameliorate chronic inflammatory disorders including rheumatoid arthritis, systemic lupus erythematosus, and atherosclerosis. However, its in vivo effect on intestinal inflammation remains unknown. Here we evaluated the protective and therapeutic potentials of AS605240 in mice with dextran sodium sulfate (DSS)-induced acute and chronic colitis. Our results showed that AS605240 improved survival rate, disease activity index, and histological damage score in mice administered DSS in both preventive and therapeutic studies. AS605240 treatment also significantly inhibited the increase in myeloperoxidase levels, macrophage infiltration, and CD4(+) T-cell number in the colon of DSS-fed mice. The DSS-induced overproduction of colonic proinflammatory cytokines including interleukin (IL)-1beta, tumor necrosis factor-alpha, and interferon-gamma was significantly suppressed in mice undergoing AS605240 therapy, whereas colonic anti-inflammatory cytokines such as IL-4 were up-regulated. The down-regulation of the phospho-Akt level in immunological cells from the inflamed colon tissue and spleen of AS605240-treated mice was detected both by immunohistochemical analysis and Western blotting. These findings demonstrate that AS605240 may represent a promising novel agent for the treatment of inflammatory bowel disease by suppressing leukocyte infiltration as well as by immunoregulating the imbalance between proinflammatory and anti-inflammatory cytokines.
 ...
PMID:Inhibition of phosphoinositide 3-kinase ameliorates dextran sodium sulfate-induced colitis in mice. 1982 78

Interleukin (IL)-23 is a heterodimeric cytokine composed of the IL-23-specific subunit p19 and the p40 subunit which also constitutes part of IL-12. IL-23 propagates development of Th17 cells, a novel T cell subset which produces IL-17 but no interferon-gamma or IL-4. For both, IL-23 and IL-23-driven IL-17, a crucial role in autoimmune diseases such as experimental autoimmune encephalomyelitis, collagen-induced arthritis, and colitis is well accepted. Recent studies indicate that there is also a role for IL-23 and IL-17 in tumorigenesis, promoting tumor growth and vascularization, and affecting tumor incidence. We show that human CD14(+) peripheral blood monocyte-derived dendritic cells (DC), as used for clinical applications in anti-tumor immunization strategies, produce high amounts of IL-23. CD40-triggering of immature and mature DC but not of primary monocytes induced a rapid expression of high levels of IL-23, free p40, and minor levels of IL-12. Upon stimulation of DC subsets with a variety of different danger signals such as single stranded and double stranded RNA, bacterial components or viral infections, IL-23 expression pattern was analyzed. Interestingly, co-stimulation with CD40L enabled IL-23 expression by DC subsets towards danger signals to which they have been unresponsive upon single stimulation. Furthermore, we detected two novel splice variants of the IL-23-specific subunit p19 that could be associated with the regulation of IL-23 expression. Data presented here might have an impact on DC-based cancer vaccination strategies and contribute to a better understanding of the complex regulation of the heterodimeric cytokine IL-23.
 ...
PMID:CD40 ligand-triggered human dendritic cells mount interleukin-23 responses that are further enhanced by danger signals. 2007 Oct 30

Inflammatory cytokines have been proposed to regulate epithelial homeostasis during intestinal inflammation. We report here that interferon-gamma (IFN-gamma) regulates the crucial homeostatic functions of cell proliferation and apoptosis through serine-threonine protein kinase AKT-beta-catenin and Wingless-Int (Wnt)-beta-catenin signaling pathways. Short-term exposure of intestinal epithelial cells to IFN-gamma resulted in activation of beta-catenin through AKT, followed by induction of the secreted Wnt inhibitor Dkk1. Consequently, we observed an increase in Dkk1-mediated apoptosis upon extended IFN-gamma treatment and reduced proliferation through depletion of the Wnt coreceptor LRP6. These effects were enhanced by tumor necrosis factor-alpha (TNF-alpha), suggesting synergism between the two cytokines. Consistent with these results, colitis in vivo was associated with decreased beta-catenin-T cell factor (TCF) signaling, loss of plasma membrane-associated LRP6, and reduced epithelial cell proliferation. Proliferation was partially restored in IFN-gamma-deficient mice. Thus, we propose that IFN-gamma regulates intestinal epithelial homeostasis by sequential regulation of converging beta-catenin signaling pathways.
 ...
PMID:Interferon-gamma regulates intestinal epithelial homeostasis through converging beta-catenin signaling pathways. 2059 25


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>