A novel triterpenoid induces transforming growth factor beta production by intraepithelial lymphocytes to prevent ileitis.
OBJECTIVE
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Minns
Laurie A
LA
Department of Medicine, Dartmouth Medical School, Lebanon, New Hampshire 03756, USA.
Buzoni-Gatel
Dominique
D
Ely
Kenneth H
KH
Rachinel
Nicolas
N
Luangsay
Souphalone
S
Kasper
Lloyd H
LH
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage*; D016207:Cytokines / Q000187:drug effects / Q000276:immunology; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D005260:Female; D007079:Ileitis / Q000469:parasitology* / Q000517:prevention & control; D007274:Injections, Intraperitoneal; D008214:Lymphocytes / Q000187:drug effects / Q000276:immunology; D051379:Mice; D023421:Models, Animal; D009828:Oleanolic Acid / Q000008:administration & dosage* / Q000031:analogs & derivatives*; D015398:Signal Transduction / Q000276:immunology; D014123:Toxoplasmosis / Q000150:complications*; D016212:Transforming Growth Factor beta / Q000187:drug effects* / Q000502:physiology
C116817:2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid; D000894:Anti-Inflammatory Agents, Non-Steroidal; D016207:Cytokines; D016212:Transforming Growth Factor beta; D009828:Oleanolic Acid