A novel PPAR gamma gene therapy to control inflammation associated with inflammatory bowel disease in a murine model.
OBJECTIVE
Peroxisome proliferator-activated receptor gamma (PPAR gamma) is one of the nuclear receptors that plays a central role in adipocyte differentiation and insulin sensitivity. PPAR gamma has also recently been recognized as an endogenous regulator of intestinal inflammation. However, its levels are decreased during chronic inflammation in human and mice, thus limiting PPAR gamma ligand therapy during established disease. We sought to determine whether this decrease in PPAR gamma could be counteracted by a gene therapy approach.


METHODS
We characterized PPAR gamma levels in experimental colitis associated with dextran sodium sulfate administration to mice. In this model, the therapeutic benefits of PPAR gamma gene therapy using a replication-deficient adenovirus vector expressing PPAR gamma (Ad-PPAR gamma) was assessed.


RESULTS
PPAR gamma protein levels were decreased in whole colonic tissue, lamina propria lymphocytes, and peritoneal exudate cells during the course of colitis. PPAR gamma gene delivery using Ad-PPAR gamma restored responsiveness to a PPAR gamma ligand, resulting in marked amelioration of tissue inflammation associated with the colitis, which included attenuation of intercellular adhesion molecule-1, cyclooxygenase-2 and tumor necrosis factor-alpha expression.


CONCLUSIONS
Our results suggest that gene delivery of PPAR gamma can be used to restore and/or enhance endogenous anti-inflammatory processes that are normally operative in mammalian tissues such as in the colon.
Department of Biopharmaceutics, Graduate School of Biopharmaceutical Science, Osaka University, Japan.
Kazufumi
K
Katayama
Koichiro
K
Wada
Atsushi
A
Nakajima
Hiroyuki
H
Mizuguchi
Takao
T
Hayakawa
Shinsaku
S
Nakagawa
Takashi
T
Kadowaki
Ryozo
R
Nagai
Yoshinori
Y
Kamisaki
Richard S
RS
Blumberg
Tadanori
T
Mayumi
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001483:Base Sequence; D003092:Colitis / Q000276:immunology / Q000473:pathology / Q000628:therapy; D051546:Cyclooxygenase 2; D004195:Disease Models, Animal; D015870:Gene Expression / Q000276:immunology; D015316:Genetic Therapy / Q000379:methods*; D015212:Inflammatory Bowel Diseases / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics; D007527:Isoenzymes / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
D007527:Isoenzymes; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases