Impaired expression of peroxisome proliferator-activated receptor gamma in ulcerative colitis.
OBJECTIVE
The peroxisome proliferator-activated receptor gamma (PPAR gamma) has been proposed as a key inhibitor of colitis through attenuation of nuclear factor kappa B (NF-kappa B) activity. In inflammatory bowel disease, activators of NF-kappa B, including the bacterial receptor toll-like receptor (TLR)4, are elevated. We aimed to determine the role of bacteria and their signaling effects on PPAR gamma regulation during inflammatory bowel disease (IBD).


METHODS
TLR4-transfected Caco-2 cells, germ-free mice, and mice devoid of functional TLR4 (Lps(d)/Lps(d) mice) were assessed for their expression of PPAR gamma in colonic tissues in the presence or absence of bacteria. This nuclear receptor expression and the polymorphisms of gene also were assessed in patients with Crohn's disease (CD) and ulcerative colitis (UC), 2 inflammatory bowel diseases resulting from an abnormal immune response to bacterial antigens.


RESULTS
TLR4-transfected Caco-2 cells showed that the TLR4 signaling pathway elevated PPAR gamma expression and a PPAR gamma-dependent reporter in an I kappa kappa beta dependent fashion. Murine and human intestinal flora induced PPAR gamma expression in colonic epithelial cells of control mice. PPAR gamma expression was significantly higher in the colon of control compared with Lps(d)/Lps(d) mice. Although PPAR gamma levels appeared normal in patients with CD and controls, UC patients displayed a reduced expression of PPAR gamma confined to colonic epithelial cells, without any mutation in the PPAR gamma gene.


CONCLUSIONS
These data showed that the commensal intestinal flora affects the expression of PPAR gamma and that PPAR gamma expression is considerably impaired in patients with UC.
Equipe Propre INSERM 0114 sur la Physiopathologie des Maladies Inflammatoires Intestinales, Lille, France.
Laurent
L
Dubuquoy
Emmelie A
EA
Jansson
Samir
S
Deeb
Sabine
S
Rakotobe
Mehdi
M
Karoui
Jean-Frédéric
JF
Colombel
Johan
J
Auwerx
Sven
S
Pettersson
Pierre
P
Desreumaux
D000818:Animals; D018938:Caco-2 Cells; D003093:Colitis, Ulcerative / Q000503:physiopathology*; D003106:Colon / Q000166:cytology / Q000503:physiopathology; D029721:Drosophila Proteins; D004755:Enterobacteriaceae; D004847:Epithelial Cells / Q000166:cytology / Q000502:physiology; D005260:Female; D015870:Gene Expression / Q000502:physiology; D006801:Humans; D007413:Intestinal Mucosa / Q000166:cytology / Q000382:microbiology / Q000503:physiopathology; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008809:Mice, Inbred C3H; D009154:Mutation; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000032:analysis; D011956:Receptors, Cell Surface / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics*; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D014157:Transcription Factors / Q000235:genetics*
D029721:Drosophila Proteins; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D018160:Receptors, Cytoplasmic and Nuclear; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D014157:Transcription Factors