Th1과 Th17 기도면역질환 치료제로써의 아세틸살리실산 (아스피린) 의 기능연구

Abstract

Asthma is a complex syndrome with many clinical phenotypes in both adults and children. Its major characteristics include a variable degree of airflow obstruction, airway hyperresponsiveness, and eosinophilic or noneosinophilic inflammation. Recently, we addressed noneosinophilic (or neutrophilic) inflammation which was associated with mixed Th1 and Th17 cell responses when the airway was exposed to lipopolysaccharide (LPS)-containing allergens. When we investigated the roles of acetylsalicylic acid (ASA) on Th1 and Th17 lung inflammation, ASA inhibited selectively Th17-type but not Th1-type lung inflammation. However, salicylic acid and celecoxib which are the analogue of ASA failed to reduce Th17 inflammation. In depth, we evaluated the role of ASA in differentiation, proliferation and maintenance phase of Th17 immune response. ASA couldn't modulate IL-6 production in macrophages and dendritic cells but suppressed CD4+IL-17A+ T cell proliferation and positive feedback of IL-6 and IL-17A, which means ASA suppresses proliferation and maintenance phase of Th17 immune response. On the other hand, ASA triggered in vitro and in vivo adenosine production by inhibiting expression of adenosine deaminase (ADA). And ASA induced adenosine receptor composition change, which adenosine receptor A1, A2a and A3 were up-regulated but A2b was down-regulated. When separated adenosine receptor signalings with receptor antagonists complexes and adenosine receptor A1, A2a and A3 signals reduced Th17-type lung inflammation. Furthermore, injected adenosine reduced Th17-type lung inflammation. Take together, ASA selectively suppresses Th17-type lung inflammation which is adenosine dependent manner and it possibly can be a promising therapeutics of Th17-type diseases.In the other hand, theophylline is commonly used to treat severe asthma and chronic obstructive pulmonary disease (COPD) characterized by non-eosinophilic (neutrophilic) inflammation. Theophylline inhibited lung inflammation partly induced by Th1 immune response. ASA attenuated the beneficial effects of theophylline. However, co-administration of the ASA metabolite salicylic acid (SA) showed no attenuating effect on theophylline treatment. The therapeutic effect of theophylline was associated with increase in cAMP levels, which was blocked by co-treatment of theophylline and ASA. ASA co-treatment also attenuated the anti-inflammatory effects of a specific phosphodiesterase (PDE) 4 inhibitor. These results demonstrate that ASA reverses anti-inflammatory effects of theophylline, and that ASA exerts its adverse effects through the inhibition of cAMP production. I suggest that ASA reverses lung inflammation in patients taking theophylline, although clinical evidence will be needed.