concanavalin-a and Inflammatory-Bowel-Diseases

Inflammatory bowel disease (IBD) is a multifactorial disorder with an unknown aetiology. The aim of this study is to employ a murine model of IBD to identify pathways and genes, which may play a key role in the pathogenesis of IBD and could be important for discovery of new disease markers in human disease. Here, we have investigated severe combined immunodeficient (SCID) mice, which upon adoptive transfer with concanavalin A-activated CD4(+) T cells develop inflammation of the colon with predominance in rectum. Mice with increasing level of inflammation was studied. RNA from rectum of transplanted and non-transplanted SCID mice was investigated by a genome-wide gene expression analysis using the Affymetrix mouse expression array 430A (MOE430A) including 22,626 probe sets. A significant change in gene expression (P = 0.00001) is observed in 152 of the genes between the non-transplanted control mice and colitis mice, and among these genes there is an overrepresentation of genes involved in inflammatory processes. Some of the most significant genes showing higher expression encode S100A proteins and chemokines involved in trafficking of leucocytes in inflammatory areas. Classification by gene clustering based on the genes with the significantly altered gene expression corresponds to two different levels of inflammation as established by the histological scoring of the inflamed rectum. These data demonstrate that this SCID T-cell transfer model is a useful animal model for human IBD and can be used for suggesting candidate genes involved in the pathogenesis and for identifying new molecular markers of chronic inflammation in human IBD.

Topics: Adoptive Transfer; Animals; Chromosome Mapping; Cluster Analysis; Colitis; Colon; Concanavalin A; Female; Gene Expression Profiling; Genome; Genome, Human; Humans; Inflammatory Bowel Diseases; Mice; Mice, Inbred BALB C; Mice, SCID; Oligonucleotide Array Sequence Analysis; Reverse Transcriptase Polymerase Chain Reaction; Synteny; T-Lymphocytes

Curcumin (diferulolylmethane) has been shown to have a protective role in mouse models of inflammatory bowel diseases (IBD) and to reduce the relapse rate in human ulcerative colitis (UC), thus making it a potentially viable supportive treatment option. Trinitrobenzene sulfonic acid (TNBS) colitis in NKT-deficient SJL/J mice has been described as Th1-mediated inflammation, whereas BALB/c mice are believed to exhibit a mixed Th1/Th2 response.. We therefore investigated the effect of dietary curcumin in colitis induced in these 2 strains.. In the BALB/c mice, curcumin significantly increased survival, prevented weight loss, and normalized disease activity. In the SJL/J mice, curcumin demonstrated no protective effects. Genomewide microarray analysis of colonic gene expression was employed to define the differential effect of curcumin in these 2 strains. This analysis not only confirmed the disparate responses of the 2 strains to curcumin but also indicated different responses to TNBS. Curcumin inhibited proliferation of splenocytes from naive BALB/c mice but not SJL/J mice when nonspecifically stimulated in vitro with concanavalin A (ConA). Proliferation of CD4(+) splenocytes was inhibited in both strains, albeit with about a 2-fold higher IC(50) in SJL/J mice. Secretion of IL-4 and IL-5 by CD4(+) lymphocytes of BALB/c mice but not SJL/J mice was significantly augmented by ConA and reduced to control levels by curcumin.. The efficacy of dietary curcumin in TNBS colitis varies in BALB/c and SJL/J mouse strains. Although the exact mechanism underlying these differences is unclear, the results suggest that the therapeutic value of dietary curcumin may differ depending on the nature of immune dysregulation in IBD.

Topics: Animals; Colitis; Concanavalin A; Curcumin; Diet; Disease Models, Animal; Inflammatory Bowel Diseases; Lymphocytes; Male; Mice; Mice, Inbred BALB C; Mice, Inbred Strains; Microarray Analysis; Reverse Transcriptase Polymerase Chain Reaction; Species Specificity; Trinitrobenzenesulfonic Acid

OX40 is a member of the TNFR superfamily, and is found predominantly on activated CD4-positive T cells. In vitro an OX40-IgG fusion protein inhibits mitogen- and Ag-driven proliferation and cytokine release by splenocytes and lymph node T cells. In contrast, an OX40 ligand-IgG fusion protein enhanced proliferative responses. In normal mice, OX40-positive cells are observed only in lymphoid tissues, including Peyer's patches of the gut. In mice with hapten-induced colitis or IL-2 knockout mice with spontaneous colitis, OX40-positive cells are found infiltrating the lamina propria. Administration of the OX40-IgG fusion protein to mice with ongoing colitis (but not the OX40 ligand-IgG) ameliorated disease in both mouse models of inflammatory bowel disease. This was evidenced by a reduction in tissue myeloperoxidase; reduced transcripts for TNF-alpha, IL-1, IL-12, and IFN-gamma; and a reduction in the T cell infiltrate. Targeting OX40 therefore shows considerable promise as a new strategy to inhibit ongoing T cell reactions in the gut.

Topics: Animals; CHO Cells; Colitis; Concanavalin A; Cricetinae; Cytokines; Epitopes, T-Lymphocyte; Female; Humans; Immunoglobulin G; Inflammatory Bowel Diseases; Injections, Intraperitoneal; Interleukin-2; Ligands; Lymphocyte Activation; Membrane Glycoproteins; Mice; Mice, Inbred BALB C; Mice, Inbred C3H; Mice, Knockout; OX40 Ligand; Receptors, OX40; Receptors, Tumor Necrosis Factor; Recombinant Fusion Proteins; T-Lymphocyte Subsets; Tumor Necrosis Factor Receptor Superfamily, Member 7; Tumor Necrosis Factors

The mechanisms underlying inflammatory bowel disease (IBD) remain obscure but the importance of inflammatory processes is clear and most pharmacological therapies inhibit inflammation. The search for more effective agents with low toxicity continues. To test the possibility that the antiinflammatory/anticytokine peptide alpha-MSH can be used to control IBD, the peptide was administered to a murine colitis model. The peptide treatment had marked salutary effects: it reduced the appearance of fecal blood by over 80%, inhibited weight loss, and prevented disintegration of the general condition of the animals. Mice given alpha-MSH showed markedly lower production of TNF alpha by tissues of the lower colon stimulated with concanavalin A; the inhibitory effect of alpha-MSH on production of inflammatory nitric oxide by lower bowel tissue was even greater. The combined results indicate that alpha-MSH modulates experimental IBD, perhaps by inhibiting production within the gut of the local proinflammatory agents TNF alpha and nitric oxide, or by inhibiting inflammatory processes closely linked to these mediators.

Topics: alpha-MSH; Animals; Concanavalin A; Dextran Sulfate; Disease Models, Animal; Gastrointestinal Hemorrhage; Inflammatory Bowel Diseases; Intestine, Large; Male; Mice; Mice, Inbred BALB C; Nitric Oxide; Occult Blood; Tumor Necrosis Factor-alpha; Weight Loss