Production of IL-1 and IL-1 receptor antagonist and the pathological significance in lipopolysaccharide-induced arthritis in rabbits.
Injection of lipopolysaccharide (LPS) into rabbit knee joints provoked leucocyte infiltration and loss of proteoglycan (PG) from the cartilage. We investigated the role of IL-1 and IL-1 receptor antagonist (IL-1Ra) and its significance in the pathogenesis of LPS-arthritis. Production of IL-1 beta peaked at 6 h (196.7 +/- 89.4 pg/joint) after injection of 10 ng of LPS, while IL-1Ra peaked at 9 h (34.5 +/- 13.4 ng/joint). The amount of IL-1Ra was 180-200-fold molar excess of IL-1, and a large amount of IL-1Ra was sustained for 1 week. Both IL-1 beta and IL-1Ra were mainly produced by synovial exudate cells. Arthritis was reproduced by rabbit IL-1 beta. LPS-induced leucocyte infiltration was inhibited 70-75% by rabbit IL-1Ra. Loss of PG in LPS-arthritis was prevented by IL-1Ra and also by neutrophil elastase inhibitor, and superoxide dismutase. In leucopenic rabbits, injection of LPS induced neither production of IL-1 beta nor loss of PG. Direct injection of inflammatory exudated cells in leucopenic rabbits reproduced loss of PG, and there was only a partial recovery by IL-1Ra. These results suggest that LPS-initiated IL-1 acts as a key mediator in LPS-arthritis and that endogenous IL-1Ra may suppress a part of IL-1 activity at the site, but its amount was too low for suppression of the produced IL-1. Loss of PG is a sequela of infiltrated leucocytes and leucocyte-derived elastase, and superoxide anion may play a pivotal role in the destruction of cartilage.
Matsukawa
A
A
Department of Pathology, Kumamoto University School of Medicine, Japan.
Ohkawara
S
S
Maeda
T
T
Takagi
K
K
Yoshinaga
M
M
D000818:Animals; D001168:Arthritis / Q000378:metabolism*; D005260:Female; D005998:Glycine / Q000031:analogs & derivatives / Q000494:pharmacology; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D019272:Leukocyte Elastase; D007970:Leukopenia / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity*; D010196:Pancreatic Elastase / Q000502:physiology; D011509:Proteoglycans / Q000378:metabolism; D011817:Rabbits; D012795:Sialoglycoproteins / Q000096:biosynthesis*; D013449:Sulfonamides / Q000494:pharmacology
D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D008070:Lipopolysaccharides; D011509:Proteoglycans; D012795:Sialoglycoproteins; D013449:Sulfonamides; C069195:sivelestat; D010196:Pancreatic Elastase; D019272:Leukocyte Elastase; D005998:Glycine