A novel transcription factor inhibitor, SP100030, inhibits cytokine gene expression, but not airway eosinophilia or hyperresponsiveness in sensitized and allergen-exposed rat.
1. We examined the effect of SP100030, a novel inhibitor of activator protein-1 (AP-1) and nuclear factor (NF)-kappa B transcription factors, in a rat model of asthma. 2. Sensitized Brown-Norway rats were treated with SP100030 (20 mg kg(-1) day(-1) for 3 days) intraperitoneally prior to allergen challenge. Allergen exposure of sensitized rats induced bronchial hyperresponsiveness (BHR), accumulation of inflammatory cells in bronchoalveolar lavage (BAL) fluid, and also an increase in eosinophils and CD2(+), CD4(+) and CD8(+) T-cells in the airways together with mRNA expression for IL-2, IL-4, IL-5, IL-10, and IFN-gamma. 3. Pre-treatment with SP100030 inhibited BAL lymphocyte influx (P<0.03), specifically reduced CD8(+) T-cell infiltration in the airway submucosa (P<0.03), and mRNA expression for IL-2, IL-5, and IL-10 (P<0.05). Neutrophil, eosinophil, and CD4(+) T-cells accumulation in the airways and BHR were not affected by SP100030. 4. Our results indicate that suppression of IL-2 and IL-5 mRNA expression may not necessarily lead to suppression of BHR. The expression of IL-5 mRNA may contribute to the airway accumulation of eosinophils, but does not correlate with the extent of eosinophilia. 5. The joint AP-1 and NF-kappa B inhibitor, SP100030, selectively inhibits CD8(+) T-cells, and mRNA expression of both Th1 and Th2 cytokines in vivo, but does not inhibit allergen-induced airway eosinophilia and BHR.
Huang
T J
TJ
Thoracic Medicine, Chang Gung Memorial Hospital, Keelung Branch, Taiwan, Republic of China.
Adcock
I M
IM
Chung
K F
KF
D000485:Allergens / Q000276:immunology*; D000818:Animals; D015153:Blotting, Western; D016535:Bronchial Hyperreactivity / Q000235:genetics / Q000276:immunology / Q000517:prevention & control*; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D018801:CD2 Antigens / Q000032:analysis; D015704:CD4 Antigens / Q000032:analysis; D016827:CD8 Antigens / Q000032:analysis; D016207:Cytokines / Q000235:genetics*; D004804:Eosinophils / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D005786:Gene Expression Regulation / Q000187:drug effects; D007150:Immunohistochemistry; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007371:Interferon-gamma / Q000235:genetics; D016753:Interleukin-10 / Q000235:genetics; D007376:Interleukin-2 / Q000235:genetics; D015847:Interleukin-4 / Q000235:genetics; D015848:Interleukin-5 / Q000235:genetics; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D008214:Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D008297:Male; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D009930:Organic Chemicals; D010047:Ovalbumin / Q000276:immunology; D016755:Proto-Oncogene Proteins c-jun / Q000187:drug effects / Q000378:metabolism; D011657:Pulmonary Eosinophilia / Q000235:genetics / Q000276:immunology / Q000517:prevention & control*; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011914:Rats, Inbred BN; D020545:Respiratory Mucosa / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D013047:Specific Pathogen-Free Organisms; D018808:Transcription Factor AP-1 / Q000037:antagonists & inhibitors; D014157:Transcription Factors / Q000037:antagonists & inhibitors*; D000813:Anilides; D001549:Benzamides; D011743:Pyrimidines
D000485:Allergens; D018801:CD2 Antigens; D015704:CD4 Antigens; D016827:CD8 Antigens; D016207:Cytokines; D007166:Immunosuppressive Agents; D007371:Interferon-gamma; D016753:Interleukin-10; D007376:Interleukin-2; D015847:Interleukin-4; D015848:Interleukin-5; D016328:NF-kappa B; D009930:Organic Chemicals; D010047:Ovalbumin; D016755:Proto-Oncogene Proteins c-jun; D012333:RNA, Messenger; D018808:Transcription Factor AP-1; D014157:Transcription Factors; C102914:N-(3,5-bis(trifluoromethyl)phenyl)-2-chloro-4-(trifluoromethyl)pyrimidine-5-carboxamide; D000813:Anilides; D001549:Benzamides; D011743:Pyrimidines