Human adenosine deaminase 2 induces differentiation of monocytes into macrophages and stimulates proliferation of T helper cells and macrophages

Abstract

ADAs play a pivotal role in regulating the level of adenosine, a signaling molecule controlling a variety of cellular responses by binding to and activating four ADRs. Two enzymes, ADA1 and ADA2, are known to possess ADA activity in humans. Although the structure of ADA1 and its role in lymphocytic activation have been known for a long time, the structure and function of ADA2, a member of ADGF, remain enigmatic. Here, we found that ADA2 is secreted by monocytes undergoing differentiation into macrophages or DCs and that it binds to the cell surface via proteoglycans and ADRs. We demonstrate that ADA1 and ADA2 increase the rate of proliferation of monocyte-activated CD4+ T cells independently of their catalytic activity. We also show that ADA2 induces T cell-dependent differentiation of monocytes into macrophages and stimulates macrophage proliferation. Our discovery of the growth factor-like activity of ADA2 explains clinical observations and suggests that this enzyme could be used as a drug candidate to modulate the immune responses during inflammation and cancer.

Role of Purine Metabolism Enzymes in Immune Pathogenesis of Fibro-Cavernous Pulmonary Tuberculosis

“…АДА-2 экспрессируется моноцитами/макро-фагами в ответ на инвазию патогенов (Mtb) в ме-ста с высокой концентрацией аденозина и низким pH [15]. У больных ФКТ по отсутствию связей между показателями АДА сыворотки и монону-клеаров можно предположить, что рост активно-сти внеклеточной АДА-2 происходит вследствие разрушения (лизиса) макрофагов.…”

“…Ключе-вые ферменты пуринового метаболизма -адено-зиндезаминаза (АДА и ее изоферменты -АДА-1 и АДА-2) и экто-5'-нуклеотидаза (5'-НК), кон-тролирующие уровень аденозина, играют важную роль в регуляции клеточного иммунитета [7]. АДА-1 увеличивает пролиферацию CD4 + T-клеток, стимулирует пролиферацию антиген-активи-рованных Т-клеток, продуцирующих IFNγ [15]. АДА-1 -в комплексе с протеином, идентифици-рованная как дипептидилпептидаза IV (DPPIV), присутствует в качестве эктоэнзима на различных клетках [6].…”

“…АДА-2 увеличивает пролиферацию CD4 + T-клеток, индуцирует дифференциацию моноцитов в макрофаги с последующей пролиферацией ма-крофагов. Уровень секреции АДА-2 макрофагами ингибирует IFNγ [15].…”

Update on genetics and pathogenesis of autoinflammatory diseases: the last 2 years

“…The disruption of cecr1a expression in mpx-GFP transgenic fish causes a marked reduction in neutrophil numbers. ADA2 is known to induce T-cell-dependent differentiation of monocytes into macrophages [12]. These observations suggest a role for ADA2 in differentiation of endothelial and myeloid cells.…”

Evaluating of Serum Adenosine Deaminase Isoenzymesin Lung Contusion

“…ADA2 normally has a much lower capacity to catalyze adenosine deamination than ADA1 [16]. ADA2 enzyme activity becomes optimal at high levels of adenosine, low pH and inflammation conditions [17,18], that can associated with lung cuntusion injury. We found that ADA2 became predominant isoenzyme in serum, which may be due to active tissue macrophages during lung contusion.…”