transforming-growth-factor-beta and Ileitis

Signaling of 17β-estradiol (estrogen) through its two nuclear receptors, α and β (ERα, ERβ), is an important mechanism of transcriptional regulation. Although ERs are broadly expressed by cells of the immune system, the mechanisms by which they modulate immune responses remain poorly understood. ERβ-specific signaling is reduced in patients with chronic inflammatory diseases, including systemic lupus erythematosus and inflammatory bowel disease, and our previous work suggests that dysregulation of ERβ-specific signaling contributes to enhanced intestinal inflammation in female SAMP/YitFC mice, a spontaneous model of Crohn's disease-like ileitis. The present study builds on these prior observations to identify a nonredundant, immunoprotective role for ERβ-specific signaling in TGF-β-dependent regulatory T cell (Treg) differentiation. Using a strain of congenic SAMP mice engineered to lack global expression of ERβ, we observed dramatic, female-specific exacerbation of intestinal inflammation accompanied by significant reductions in intestinal Treg frequency and function. Impaired Treg suppression in the absence of ERβ was associated with aberrant overexpression of

Topics: Adolescent; Adult; Animals; Crohn Disease; Disease Models, Animal; Estrogen Receptor alpha; Estrogen Receptor beta; Estrogens; Female; Glucocorticoids; Humans; Ileitis; Inflammation; Inflammatory Bowel Diseases; Intestines; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Middle Aged; Signal Transduction; T-Lymphocytes, Regulatory; Transcription Factors; Transforming Growth Factor beta; Young Adult

Intraepithelial lymphocytes (IEL) play a key role in gut homeostasis and are critical effector cells preventing the inflammatory intestinal lesions induced in mice following oral infection with Toxoplasma gondii. In this intestinal inflammatory model, CD4(+) T lymphocytes from the lamina propria (LP) synergize with the infected enterocytes to secrete pro-inflammatory chemokines and cytokines. In this study, we assessed the mechanisms accounting for the ability of IEL to modulate the inflammatory activity of these cells. Adoptive transfer of IEL purified from wild-type mice, or CD154-,CD95L- or IL-10-deficient mice infected with T. gondii completely impairs the development of the lethal ileitis in recipient mice orally infected with T. gondii. Compared with unprimed IEL isolated from naive mice, the CD8 alpha beta TCR alpha beta subset of primed IEL, isolated from T. gondii-infected mice, secretes increased amount of TGF-beta. IEL interact with the LP CD4(+) T lymphocytes, down-regulate their production of inflammatory cytokines such as IFN-gamma and reduce their proliferative activity. These effects are linked to the secretion of TGF-beta and are correlated with a shift in the balance between Smad7/T-bet down-regulation and Smad2/Smad3 up-regulation in LP CD4(+) T lymphocytes.

Topics: Adoptive Transfer; Animals; DNA-Binding Proteins; Female; Ileitis; Immunoblotting; Inflammation; Intestinal Mucosa; Intestines; Mice; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction; Smad Proteins; T-Lymphocytes; Toxoplasma; Toxoplasmosis; Trans-Activators; Transforming Growth Factor beta

The loss of homeostasis is a hallmark of inflammatory bowel disease. Oral infection of susceptible mice with Toxoplasma gondii results in an acute lethal ileitis characterized by increased interferon gamma, tumor necrosis factor alpha, and inducible nitric oxide synthase; homeostasis results from transforming growth factor beta production by intraepithelial lymphocytes. The synthetic oleanane triterpenoid 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO) is a potent anti-inflammatory molecule previously shown in vitro to suppress the de novo synthesis of inducible nitric oxide synthase and to induce the transcription and activation of genes from the transforming growth factor beta signaling pathway.. We evaluated the immune response in the small intestine and by intraepithelial lymphocytes after a single intraperitoneal dose of CDDO at the time of T. gondii oral infection. We abrogated the homeostatic effects of CDDO by blocking transforming growth factor beta in vivo.. CDDO acid prevented ileitis development through the global down-regulation of inflammatory cytokines and chemokines. Total transforming growth factor beta(1) production by the intraepithelial lymphocytes increased, as did Smad2 expression. Blocking transforming growth factor beta reversed CDDO-induced protection and prevented the up-regulation of Smad2 in the small intestine.. CDDO acid is a novel anti-inflammatory molecule capable of preventing ileitis by activating the transforming growth factor beta signaling pathway in a pathogen-driven ileitis model. This could represent a new treatment of inflammatory bowel disease.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Cytokines; Down-Regulation; Female; Ileitis; Injections, Intraperitoneal; Lymphocytes; Mice; Models, Animal; Oleanolic Acid; Signal Transduction; Toxoplasmosis; Transforming Growth Factor beta

Acute inflammatory ileitis occurs in susceptible (C57BL/6) mice after oral infection with Toxoplasma gondii. Overproduction of interferon (IFN)-gamma and synthesis of nitric oxide mediate the inflammation. We evaluated the role of transforming growth factor (TGF)-beta produced by intraepithelial lymphocytes (IELs) in this process.. We analyzed the histologic and immunologic consequences of adoptive transfer of antigen-primed IELs into susceptible mice treated with anti-TGF-beta before oral challenge with T. gondii cysts. An in vitro coculture of enterocytes and IELs assessed the production of chemokines and cytokines in the presence of anti-TGF-beta.. Antigen-primed IELs prevent acute ileitis in susceptible mice that is reversed with anti-TGF-beta. Resistant mice (CBA/J) develop ileitis after treatment with anti-TGF-beta. Antigen-primed IELs can induce systemic immunosuppression as measured by depressed IFN-gamma production. In vitro, primed IELs reduce the production of inflammatory chemokines by infected enterocytes and IFN-gamma by splenocytes.. Regulation of the ileal inflammatory process resulting from T. gondii is dependent on TGF-beta-producing IELs. The IELs are an essential component in gut homeostasis after oral infection with this parasite.

Topics: Animals; Chemokines; Disease Susceptibility; Down-Regulation; Enterocytes; Female; Ileitis; Inflammation Mediators; Intestinal Mucosa; Lymphocytes; Mice; Mice, Inbred C57BL; Mice, Inbred CBA; Toxoplasma; Toxoplasmosis; Transfection; Transforming Growth Factor beta