A novel transcription factor inhibitor, SP100030, inhibits cytokine gene expression, but not airway eosinophilia or hyperresponsiveness in sensitizedand allergen-exposed rat

1 We examined the effect of SP100030, a novel inhibitor of activator protei n-1 (AP-1) and nuclear factor (NF)-kappaB transcription factors, in a rat m odel 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 ex posure of sensitized rats induced bronchial hyperresponsiveness (BHR), accu mulation of inflammatory cells in bronchoalveolar lavage (BAL) fluid, and a lso 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), sp ecifically 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 ma y not necessarily lead to suppression of BHR. The expression of IL-5 mRNA m ay contribute to the airway accumulation of eosinophils, but does not corre late with the extent of eosinophilia. 5 The joint AP-1 and NF-kappaB inhibitor, SP100030, selectively inhibits CD 8(+) T-cells, and MRNA expression of both Th1 and Th2 cytokines in vivo, bu t does not inhibit allergen-induced airway eosinophilia and BHR.