Effect of an inhibitor of Jun N-terminal protein kinase, SP600125, in single allergen challenge in sensitized rats.
Jun N-terminal kinase (JNK) has been implicated in the pathogenesis of inflammatory diseases including asthma. We examined the effect of SP600125 (anthra [1,9-cd] pyrazol-6 (2H)-one), a novel inhibitor of JNK in a model of asthma. Brown-Norway rats were sensitized to ovalbumin and treated with SP600125 intraperitoneally (90 mg/kg in total). SP600125 inhibited allergen-induced, increased activity of phosphorylated c-jun but not of phosphorylated-MAPKAPK2, indicative of activation of p38 MAPK, in the lung. SP600125 inhibited macrophage (P < 0.04), lymphocyte (P < 0.05), eosinophil (P < 0.04) and neutrophil (P < 0.005) numbers in bronchoalveolar lavage. Eosinophil and T-cell accumulation in the airways, mRNA expression for interleukin-1beta, tumour necrosis factor-beta, interleukin-3, interleukin-4 and interleukin-5, serum levels of allergen-specific immunoglobulin E and bronchial hyperresponsiveness were not affected by SP600125. Selective inhibition of JNK reduced inflammatory cell egress into the airway lumen after single allergen exposure. The role of JNK mitogen-activated protein kinase activation may be limited in the pathogenesis of bronchial hyperresponsiveness after single allergen exposure.
Eynott
Paul R
PR
Thoracic Medicine, National Heart and Lung Institute, Imperial College School of Medicine, London, UK.
Xu
Li
L
Bennett
Brydon L
BL
Noble
Alistair
A
Leung
Sum-Yee
SY
Nath
Puneeta
P
Groneberg
David A
DA
Adcock
Ian M
IM
Chung
K Fan
KF
D000485:Allergens / Q000494:pharmacology*; D000818:Animals; D000873:Anthracenes / Q000494:pharmacology*; D001249:Asthma / Q000276:immunology*; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D002452:Cell Count; D016207:Cytokines / Q000276:immunology; D004789:Enzyme Activation; D004804:Eosinophils / Q000276:immunology; D048031:JNK Mitogen-Activated Protein Kinases; D007958:Leukocyte Count; D007963:Leukocytes, Mononuclear / Q000276:immunology; D008168:Lung / Q000201:enzymology / Q000276:immunology*; D048670:MAP Kinase Kinase 4; D008264:Macrophages / Q000276:immunology; D008297:Male; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D023421:Models, Animal; D009504:Neutrophils / Q000276:immunology; D010047:Ovalbumin; D051381:Rats; D011914:Rats, Inbred BN; D048051:p38 Mitogen-Activated Protein Kinases
D000485:Allergens; D000873:Anthracenes; D016207:Cytokines; C432165:pyrazolanthrone; D010047:Ovalbumin; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases