Adenosine-mediated inhibition of cytotoxic activity and cytokine production by IL-2/NKp46-activated NK cells: involvement of protein kinase A isozyme I (PKA I).
Adenosine suppresses the production of various cytokines/ chemokines and inhibits the cytotoxic activity of murine and human NK cells activated with IL-2 or Ly49D, NKp46-receptor crosslinking, respectively. These effects are mediated by the type A2A adenosine receptor via stimulation of adenylyl cyclase, increased production of cAMP, and activation of PKA. PKA I, but not PKA II, participates in the inhibitory effects of adenosine. Blocking regulatory, but not catalytic, subunits of PKA I abrogates the inhibitory effects of adenosine. These findings suggest that tumor-produced adenosine inhibits the activity of NK and other effector cells and thereby protects tumors from immune-mediated destruction.
Raskovalova
Tatiana
T
Department of Pathology, University of Pittsburgh, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213, USA.
Lokshin
Anna
A
Huang
Xiaojun
X
Jackson
Edwin K
EK
Gorelik
Elieser
E
D000241:Adenosine / Q000276:immunology* / Q000378:metabolism; D000818:Animals; D017868:Cyclic AMP-Dependent Protein Kinases / Q000276:immunology* / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis; D003602:Cytotoxicity, Immunologic; D006801:Humans; D007376:Interleukin-2 / Q000378:metabolism; D007527:Isoenzymes / Q000276:immunology / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism; D055627:Natural Cytotoxicity Triggering Receptor 1; D009369:Neoplasms / Q000276:immunology; D043683:Receptors, Adenosine A2 / Q000276:immunology* / Q000378:metabolism; D011971:Receptors, Immunologic / Q000378:metabolism; D019139:Tumor Escape
D016207:Cytokines; D007376:Interleukin-2; D007527:Isoenzymes; D008562:Membrane Glycoproteins; C112260:NCR1 protein, human; D055627:Natural Cytotoxicity Triggering Receptor 1; D043683:Receptors, Adenosine A2; D011971:Receptors, Immunologic; D017868:Cyclic AMP-Dependent Protein Kinases; D000241:Adenosine