Human adenosine deaminase 2 induces differentiation of monocytes into macrophages and stimulates proliferation of T helper cells and macrophages.
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.
Zavialov
Andrey V
AV
Institut National de la Santé et de la Recherche Médicale U924, Univesity of Nice-Sophia Antipolis, Valbonne, France. andrey.zavialov@gmail.com
Gracia
Eduard
E
Glaichenhaus
Nicolas
N
Franco
Rafael
R
Zavialov
Anton V
AV
Lauvau
Grégoire
G
D056704:Adaptive Immunity; D000243:Adenosine Deaminase / Q000378:metabolism / Q000502:physiology*; D002454:Cell Differentiation; D002460:Cell Line; D049109:Cell Proliferation; D006801:Humans; D007113:Immunity, Innate; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism / Q000502:physiology*; D008264:Macrophages / Q000166:cytology*; D009000:Monocytes / Q000166:cytology*; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*
D036341:Intercellular Signaling Peptides and Proteins; C408373:ADA2 protein, human; D000243:Adenosine Deaminase