Modulation of cytokine release by purine receptors in patients with rheumatoid arthritis.
OBJECTIVE
Since adenosine receptors are known to modulate the release of some inflammatory mediators in control subjects, we have examined the effects of the mixed A1 and A2 adenosine receptor agonist 5'-N-ethylcarboxamidoadenosine (NECA) on basal and lipopolysaccharide (LPS)-induced cytokine release in diluted whole blood cultures from rheumatoid arthritis (RA) patients and healthy volunteers.


METHODS
Twenty-eight patients with rheumatoid arthritis aged 18-75 years gave their voluntary consent to participate and give a blood sample. Basal levels of tumour necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta) and interleukin-6 (IL-6) were measured by ELISA, and whole blood cultures were prepared to assess the effects of LPS activation.


RESULTS
Following a 40-hour incubation, activation of adenosine receptors by NECA, added to the cell cultures from rheumatoid arthritis patients, was found to suppress both the basal and LPS-induced release of TNF-alpha and IL-1beta, while causing an increase in the release of both basal and LPS-induced IL-6. In healthy volunteers basal cytokines were undetectable, but NECA alone induced the release of all three cytokines. Stimulated levels of TNF-alpha were more than double those in patients. In the control blood cultures, NECA suppressed LPS-induced release of TNF-alpha and IL-1beta, but increased IL-6 release.


CONCLUSIONS
Adenosine receptor stimulation has a differential effect on the release of pro-inflammatory cytokines, and may induce cytokine release in normal subjects. Stimulated release of TNF-alpha is substantially lower in patients with rheumatoid arthritis than in control subjects, possibly indicating saturation, exhaustion or down-regulation of the release process.
Forrest
C M
CM
Institute of Biomedical & Life Sciences, University of Glasgow, Glasgow. C.M.Forrest@bio.gla.ac.uk
Harman
G
G
McMillan
R B
RB
Stoy
N
N
Stone
T W
TW
Darlington
L G
LG
D019830:Adenosine-5'-(N-ethylcarboxamide) / Q000276:immunology; D000293:Adolescent; D000328:Adult; D000368:Aged; D001172:Arthritis, Rheumatoid / Q000276:immunology*; D016207:Cytokines / Q000096:biosynthesis / Q000097:blood / Q000276:immunology*; D005260:Female; D006801:Humans; D007375:Interleukin-1 / Q000276:immunology; D015850:Interleukin-6 / Q000276:immunology; D008070:Lipopolysaccharides / Q000276:immunology; D008297:Male; D008875:Middle Aged; D018047:Receptors, Purinergic P1 / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology
D016207:Cytokines; D007375:Interleukin-1; D015850:Interleukin-6; D008070:Lipopolysaccharides; D018047:Receptors, Purinergic P1; D014409:Tumor Necrosis Factor-alpha; D019830:Adenosine-5'-(N-ethylcarboxamide)