Down regulation of interleukin 1beta production in human osteoarthritic synovial tissue and cartilage cultures by aminoguanidine.
OBJECTIVE
To evaluate the effect of aminoguanidine (AG) on de novo interleukin 1beta (IL1beta), nitric oxide (NO), and interleukin 1 receptor antagonist (IL1ra) production by osteoarthritic human synovial tissue and articular cartilage cultures.


METHODS
Synovial tissue and cartilage, obtained during surgery from 29 patients undergoing total knee or hip replacement for osteoarthritis, were cut into small pieces and cultured in the presence or absence of lipopolysaccharide (LPS) and test materials. IL1beta, IL1ra, and NO were determined in culture media. The inducible nitric oxide synthase inhibitor, AG, was added to cultures in various concentrations (0.3-3 mmol/l).


RESULTS
In synovial tissue cultures AG (0.3, 1, and 3 mmol/l) decreased LPS (1 microg/ml) stimulated IL1beta and NO release in the media in a dose dependent manner (p<0.05 at 1 mmol/l and p<0.05 at 0.3 mmol/l, respectively). In articular cartilage cultures AG (0.3, 1, and 3 mmol/l) decreased LPS (1 microg/ml) stimulated IL1beta and NO release in the media in a dose dependent manner (p<0.05 at 1 mmol/l and p<0.01 at 0.3 mmol/l, respectively). Hydrocortisone (5 microg/ml) also significantly decreased LPS stimulated IL1beta release in media of synovial tissue and cartilage cultures and NO in media of synovial cultures. AG (0.3, 1, and 3 mmol/l) decreased LPS (1 microg/ml) stimulated IL1ra levels in media of synovial tissue cultures in a dose dependent manner (p<0.05 at 1 mmol/l) but increased LPS (1 microg/ml) stimulated IL1ra release in media of cartilage cultures (p<0.01 at 3 mmol/l). The NO donor, nitroprusside (10, 30, 100, and 300 microg/ml) stimulated IL1beta release in media of synovial tissue cultures in a dose dependent manner (p<0.01 at 100 microg/ml). AG and nitroprusside at the concentrations used had no toxic effect on human synovial cells.


CONCLUSIONS
NO synthase inhibitors may modulate osteoarthritis and articular inflammatory processes not only by decreasing NO synthesis but also by their effects on ILbeta and IL1ra production.
Department of Rheumatology, Ichilov Hospital, Tel Aviv-Souraski Medical Centre, 6 Weizmann Street, Tel Aviv 64239, Israel.
I
I
Shirazi
I
I
Yaron
Y
Y
Wollman
M
M
Blum
T
T
Chernihovsky
R
R
Judovich
A
A
Iaina
M
M
Yaron
D000368:Aged; D002358:Cartilage, Articular / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D005938:Glucocorticoids / Q000494:pharmacology; D006146:Guanidines / Q000494:pharmacology*; D006801:Humans; D006854:Hydrocortisone / Q000494:pharmacology; D007375:Interleukin-1 / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D009599:Nitroprusside / Q000494:pharmacology; D010003:Osteoarthritis / Q000378:metabolism* / Q000473:pathology; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism; D013583:Synovial Membrane / Q000187:drug effects / Q000378:metabolism
D004791:Enzyme Inhibitors; D005938:Glucocorticoids; D006146:Guanidines; D007375:Interleukin-1; D008070:Lipopolysaccharides; D017472:Receptors, Interleukin-1; D009599:Nitroprusside; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; C004479:pimagedine; D006854:Hydrocortisone