Anti-allergic function and regulatory mechanisms of KR62980 in allergen-induced airway inflammation.
The ligand-activated transcription factor, peroxisome proliferator-activated receptor (PPAR)gamma, and its ligands inhibit pro-inflammatory cytokine production by immune cells, thus exerting anti-inflammatory activity. As a non-thiazolidinedione PPARgamma ligand, KR62980 has anti-diabetic and anti-adipogenic activities, but its anti-inflammatory function has yet to be characterized. In this study, we investigated the functions and mechanisms of KR62980 in the activation and differentiation of CD4+ T helper (Th) cells by comparing its effects with those of a thiazolidinedione PPARgamma ligand, rosiglitazone. KR62980 dose-dependently and significantly suppressed TCR-triggered Th cell proliferation by suppressing IL-2/IL-2Ralpha-mediated signaling. Both KR62980 and rosiglitazone suppressed IFNgamma production in a dose-dependent manner, whereas IL-4 gene expression was specifically suppressed by only KR62980. In addition, sustained KR62980 treatment diminished Th2 cytokine production by inhibiting c-Maf expression. In vivo administration of KR62980 in a model of allergic asthma significantly attenuated eotaxin-induced eosinophil infiltration, allergic cytokine production and collagen deposition in the lung. KR62980 also decreased goblet cell hyperplasia in the airway and mucous cell metaplasia in nasal epithelium, concurrent with decreases of allergic Th2 cytokines and IL-17 in the draining lymph node. In conclusion, a novel PPARgamma ligand, KR62980, suppresses in vitro Th2 cell differentiation and attenuates in vivo OVA-induced airway inflammation, suggesting a beneficial role for KR62980 in the treatment of allergic asthma and allergic rhinitis.
Won
Hee Yeon
HY
College of Pharmacy and Division of Life and Pharmaceutical Sciences and Center for Cell Signaling & Drug Discovery Research, Ewha Womans University, 11-1 Daehyun-Dong, Sudaemun-Ku, Seoul 120-750, Republic of Korea.
Min
Hyun Jung
HJ
Ahn
Jin Hee
JH
Yoo
Sung-Eun
SE
Bae
Myung Ae
MA
Hong
Jeong-Ho
JH
Hwang
Eun Sook
ES
D000485:Allergens; D000818:Animals; D018926:Anti-Allergic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects* / Q000378:metabolism*; D002478:Cells, Cultured; D005786:Gene Expression Regulation / Q000187:drug effects; D007192:Indenes / Q000737:chemistry / Q000494:pharmacology*; D007249:Inflammation / Q000188:drug therapy*; D053645:Interleukin-2 Receptor alpha Subunit / Q000235:genetics / Q000378:metabolism; D015847:Interleukin-4 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D015394:Molecular Structure; D009025:Morpholines / Q000737:chemistry / Q000494:pharmacology*; D010047:Ovalbumin / Q000633:toxicity; D012140:Respiratory Tract Diseases / Q000139:chemically induced* / Q000188:drug therapy; D000077154:Rosiglitazone; D018418:Th2 Cells; D045162:Thiazolidinediones / Q000494:pharmacology
C513115:1-(methylimino-N-oxy)-6-(2-morpholinoethoxy)-3-phenyl-1H-indene-2-carboxylic acid ethyl ester; D000485:Allergens; D018926:Anti-Allergic Agents; D007192:Indenes; D053645:Interleukin-2 Receptor alpha Subunit; D009025:Morpholines; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D015847:Interleukin-4; D010047:Ovalbumin