The role of adenosine receptors in regulating production of tumour necrosis factor-alpha and chemokines by human lung macrophages.
OBJECTIVE
Adenosine is a major endogenous regulator of macrophage function, and activates four specific adenosine receptors (A(1), A(2A), A(2B) and A(3)). Here, we have assessed in human lung macrophages the modulation of the expression of adenosine receptor mRNA by lipopolysaccharide (LPS), and the relative contributions of the different adenosine receptors to LPS-induced production of tumour necrosis factor (TNF)-alpha and chemokines.


METHODS
Lung macrophages isolated from resected lungs were stimulated with LPS and treated with adenosine receptor agonists or/and antagonists. Adenosine receptor expression was assessed with qRT-PCR. Cytokines were measured in lung macrophage supernatants with elisa.


RESULTS
LPS increased (about 400-fold) mRNA for A(2A) adenosine receptors, decreased mRNA for A(1) and A(2B), but had no effect on A(3) adenosine receptor mRNA. The adenosine receptor agonist NECA inhibited TNF-alpha production concentration dependently, whereas the A(1) receptor agonist, CCPA, and the A(3) receptor agonist, AB-MECA, inhibited TNF-alpha production only at concentrations affecting A(2A) receptors. NECA also inhibited the production of CCL chemokines (CCL2, CCL3, CCL4, CCL5) and CXCL chemokines (CXCL9 and CXCL10), but not that of CXCL1, CXCL8 and CXCL5. Reversal of NECA-induced inhibition of TNF-alpha and chemokine production by the selective A(2A) adenosine receptor antagonist ZM 241385, but not the A(2B) receptor antagonist, MRS 1754, or the A(3) receptor antagonist, MRS 1220, indicated involvement of A(2A) receptors.


CONCLUSIONS
LPS up-regulated A(2A) adenosine receptor gene transcription, and this receptor subtype mediated inhibition of the LPS-induced production of TNF-alpha and of a subset of chemokines in human lung macrophages.
Laboratory of Pulmonary Pharmacology UPRES EA220, Suresnes, France.
A
A
Buenestado
S
S
Grassin Delyle
I
I
Arnould
F
F
Besnard
E
E
Naline
S
S
Blouquit-Laye
A
A
Chapelier
J F
JF
Bellamy
P
P
Devillier
D000081:Acetamides / Q000494:pharmacology; D002478:Cells, Cultured; D018925:Chemokines / Q000096:biosynthesis*; D005260:Female; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D008168:Lung / Q000166:cytology; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D021122:Protein Subunits; D058906:Purinergic P1 Receptor Agonists; D058915:Purinergic P1 Receptor Antagonists; D011687:Purines / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D018047:Receptors, Purinergic P1 / Q000096:biosynthesis / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014227:Triazines / Q000494:pharmacology; D014230:Triazoles / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
C110041:9-chloro-2-(2-furyl)-5-phenylacetylamino(1,2,4)triazolo(1,5-c)quinazoline; D000081:Acetamides; D018925:Chemokines; D008070:Lipopolysaccharides; C423842:N-(4-cyanophenyl)-2-(4-(2,3,6,7-tetrahydro-2,6-dioxo-1,3-dipropyl-1H-purin-8-yl)-phenoxy)acetamide; D021122:Protein Subunits; D058906:Purinergic P1 Receptor Agonists; D058915:Purinergic P1 Receptor Antagonists; D011687:Purines; D011799:Quinazolines; D018047:Receptors, Purinergic P1; D014227:Triazines; D014230:Triazoles; D014409:Tumor Necrosis Factor-alpha; C097270:ZM 241385; C440499:lipopolysaccharide, Escherichia coli O111 B4