Upregulation of A2A adenosine receptor expression by TNF-alpha in PBMC of patients with CHF: a regulatory mechanism of inflammation.
BACKGROUND
Tumor necrosis factor (TNF)-alpha plays a role in congestive heart failure (CHF). A2A adenosine receptor (A(2A)R) activation on immune cells putatively reduces the release of cytokines contributing to CHF progression. The study is aimed at determining the role of the A(2A)R in the modulation of TNF-alpha production, and the ex vivo effect of TNF-alpha on A(2A)R in peripheral blood mononuclear cells (PBMC) from CHF patients.


RESULTS
Plasma levels of TNF-alpha and TNF-alpha production from lipopolysaccharide (LPS)-stimulated PBMC were evaluated in 26 CHF patients in comparison to controls. The effects of the A(2A)R agonist CGS-21680 and antagonist ZM-241385 on TNF-alpha production from PBMC were also evaluated. Finally, reverse transcriptase-polymerase chain reaction and Western blot analyses of A(2A)R in PBMC were performed in TNF-alpha-treated and untreated cells. TNF-alpha production from LPS-stimulated PBMC was enhanced in CHF patients with respect to controls. CGS-21680 blunted TNF-alpha production in both groups; ZM-241385 reverted this effect. A(2A)R expression in PBMC was higher in CHF patients than in controls. TNF-alpha addition produced an increase in A(2A)R in PBMC from controls but not in PBMC from CHF patients.


CONCLUSIONS
PBMC from CHF patients show an upregulation of A(2A)R-mediated inhibition of TNF-alpha, which may represents a mechanism of protection against inappropriate cytokine production.
Capecchi
Pier Leopoldo
PL
Department of Clinical Medicine and Immunological Sciences, Section of Clinical Immunology, University of Siena, Siena, Italy.
Camurri
Alessandra
A
Pompella
Gerarda
G
Mazzola
Alessia
A
Maccherini
Massimo
M
Diciolla
Francesco
F
Lazzerini
Pietro Enea
PE
Abbracchio
Maria P
MP
Laghi-Pasini
Franco
F
D000241:Adenosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D015153:Blotting, Western; D005260:Female; D006333:Heart Failure / Q000503:physiopathology*; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D009504:Neutrophils / Q000378:metabolism*; D010627:Phenethylamines / Q000494:pharmacology; D043705:Receptor, Adenosine A2A / Q000378:metabolism*; D018047:Receptors, Purinergic P1; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014227:Triazines / Q000494:pharmacology; D014230:Triazoles / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*; D015854:Up-Regulation / Q000502:physiology*
D008070:Lipopolysaccharides; D010627:Phenethylamines; D043705:Receptor, Adenosine A2A; D018047:Receptors, Purinergic P1; D014227:Triazines; D014230:Triazoles; D014409:Tumor Necrosis Factor-alpha; C097270:ZM 241385; C061282:2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine; D000241:Adenosine