title: Peroxisome proliferator-activated receptor gamma agonist ligands stimulate a Th2 cytokine response and prevent acute colitis.
abstract: Peroxisome proliferator-activated receptor gamma (PPARgamma), a member of a nuclear transcription factor family, has been previously demonstrated to have antiinflammatory activity. The effects of PPARgamma activation in the development of an immune response are less well characterized. Through evaluation of PPARgamma heterozygote mice (PPARgamma(+/-) and specific PPARgamma agonist ligand binding, we evaluated the immunologic effects of PPARgamma activation in a well-described model of colitis. Increased susceptibility to dextran sodium sulfate (DSS)-induced colitis as defined by body weights, histologic injury, and survival was observed in the PPARgamma(+/-) mice in comparison to wild-type mice. Three different PPARgamma ligands (troglitazone, pioglitazone, and rosiglitazone) demonstrated beneficial dose-related treatment effects when administered prior to the onset of colitis. However, no protection was observed when PPARgamma ligand activation occurred after the onset of colitis. The reduction in DSS-induced inflammation noted with PPARgamma ligand treatment was associated with decreased interferon-gamma and tumor necrosis factor-alpha and increased interleukin (IL)-4 and IL- 10 levels as assessed by quantitative reverse transcriptase-polymerase chain reaction. Consistent with this shift towards a T helper (Th2) cytokine dominance, PPARgamma ligand treatment stimulated increased GATA-3 expression. These results indicate that the protective effects exhibited by PPARgamma ligands in intestinal inflammation may be due to immune deviation away from Th1 and towards Th2 cytokine production.
authors.affiliation: lawrence.saubermann@bmc.org
authors.forename: Lawrence J
authors.initials: LJ
authors.lastname: Saubermann
authors.forename: Atsushi
authors.initials: A
authors.lastname: Nakajima
authors.forename: Koichiro
authors.initials: K
authors.lastname: Wada
authors.forename: Shuping
authors.initials: S
authors.lastname: Zhao
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Terauchi
authors.forename: Takashi
authors.initials: T
authors.lastname: Kadowaki
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Aburatani
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Matsuhashi
authors.forename: Ryozo
authors.initials: R
authors.lastname: Nagai
authors.forename: Richard S
authors.initials: RS
authors.lastname: Blumberg
mesh_terms: D000208:Acute Disease; D000818:Animals; D000917:Antibody Formation / Q000187:drug effects* / Q000502:physiology*; D000975:Antioxidants / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D002839:Chromans / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D003092:Colitis / Q000473:pathology / Q000503:physiopathology* / Q000517:prevention & control*; D016207:Cytokines / Q000187:drug effects* / Q000502:physiology*; D004195:Disease Models, Animal; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D008024:Ligands; D051379:Mice; D008810:Mice, Inbred C57BL; D000077205:Pioglitazone; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000627:therapeutic use; D000077154:Rosiglitazone; D018418:Th2 Cells / Q000187:drug effects* / Q000473:pathology / Q000502:physiology*; D013844:Thiazoles / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D045162:Thiazolidinediones; D014157:Transcription Factors / Q000819:agonists* / Q000494:pharmacology* / Q000627:therapeutic use; D000077288:Troglitazone
chemical_list: D000975:Antioxidants; D002839:Chromans; D016207:Cytokines; D007004:Hypoglycemic Agents; D008024:Ligands; D018160:Receptors, Cytoplasmic and Nuclear; D013844:Thiazoles; D045162:Thiazolidinediones; D014157:Transcription Factors; D000077154:Rosiglitazone; D000077288:Troglitazone; D000077205:Pioglitazone