Celastrol suppresses allergen-induced airway inflammation in a mouse allergic asthma model.
Celastrol has anti-inflammatory and immunomodulatory activities, but its anti-allergic effects remain poorly understood. Therefore, we aimed to investigate the ability of celastrol to inhibit asthmatic reactions in a mouse allergic asthma model. BALB/c mice were sensitized and challenged with ovalbumin to induce asthma. We measured the recruitment of inflammatory cells into the bronchoalveolar lavage fluid or lung tissues by Diff-Quik and hematoxylin and eosin staining, respectively, goblet cell hyperplasia by periodic acid-Schiff (PAS) staining, airway hyperresponsiveness by Flexvent system, mRNA and protein expression of cytokines, matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinases (TIMPs) by reverse transcriptase polymerase chain reaction and ELISA, respectively, and the activities of mitogen-activated protein (MAP) kinases and nuclear factor-kappa B (NF-kappaB) in the bronchoalveolar lavage cells and lung tissues by Western blot and electrophoretic mobility shift assay (EMSA), respectively. Celastrol reduced the total number of inflammatory cells in the bronchoalveolar lavage fluid and in peribronchial areas, and decreased the airway hyperresponsiveness, mRNA and protein expression levels for inflammatory cytokines such as interleukin (IL)-4, IL-13, TNF-alpha and IFN-gamma, and for MMPs and TIMPs, MAP kinases and NF-kappaB activities in the bronchoalveolar lavage cells and in the lung tissues increased in ovalbumin-induced allergic asthma in mice. Our data suggest that oral administration of celastrol suppresses ovalbumin-induced airway inflammation, hyperresponsiveness, and tissue remodeling by regulating the imbalance of MMP-2/-9 and TIMP-1/-2 by inflammatory cytokines via MAP kinases/NF-kappaB in inflammatory cells. Based on our findings, we suggest that celastrol may be used as a therapeutic agent for allergy-induced asthma.
Department of Pharmacology and Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon 440-746, Republic of Korea.
Dae Yong
DY
Kim
Jung Won
JW
Park
Dooil
D
Jeoung
Jai Youl
JY
Ro
D000485:Allergens / Q000494:pharmacology; D000818:Animals; D018927:Anti-Asthmatic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D000893:Anti-Inflammatory Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001249:Asthma / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D016207:Cytokines / Q000032:analysis; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D008168:Lung / Q000378:metabolism; D020782:Matrix Metalloproteinases / Q000032:analysis; D051379:Mice; D010047:Ovalbumin; D053978:Pentacyclic Triterpenes; D012333:RNA, Messenger / Q000378:metabolism; D013047:Specific Pathogen-Free Organisms; D014315:Triterpenes / Q000494:pharmacology* / Q000627:therapeutic use
D000485:Allergens; D018927:Anti-Asthmatic Agents; D000893:Anti-Inflammatory Agents; D016207:Cytokines; D053978:Pentacyclic Triterpenes; D012333:RNA, Messenger; D014315:Triterpenes; D010047:Ovalbumin; D020782:Matrix Metalloproteinases; C050414:celastrol