Interleukin 1 (IL-1) is a polypeptide released by activated macrophages and is thought to be a key mediator of host responses to infection and inflammation. The availability of highly purified and recombinant material has now permitted the evaluation of IL-1 as a mediator of chronic inflammatory processes in vivo. We have demonstrated that intraarticular injection of IL-1 into rabbit knee joints induces the accumulation of polymorphonuclear and mononuclear leukocytes in the joint space and the loss of proteoglycan from the articular cartilage. The effects on cartilage could not be explained solely by the presence of leukocytes, since injections ofendotoxin also stimulated leukocyte accumulation in thejoint but had no effect on proteoglycan loss. Responses to IL-1 were not associated with increased production of the icosanoids prostaglandin E2 or leukotriene B4 and were not reduced by an inhibitor of their synthesis. The pattern ofleukocyte infiltration and cartilage breakdown 24 hr after IL-1 injection was similar to that seen in animals with antigen-induced arthritis of 1 week's duration. These observations support the hypothesis that IL-1 acts directly to mediate the erosive processes of chronic arthritis.The interest in the role and biological activity of soluble products derived from mononuclear phagocytes has led to the detection of a number of factors, including endogenous pyrogen and lymphocyte-activating factor (LAF). The subsequent purification of these substances indicated a similar structural identity and the term interleukin 1 (IL-1) is now used to describe these closely related molecules (1). IL-1 plays a role in several pathophysiological events, often through the production of a secondary mediator. In the host response to infection, for example, the release of prostaglandin E2 (PGE2) by IL-1 mediates the development of fever (2). In addition, it has also been suggested that leukotrienes may be involved in IL-1-stimulated lymphocyte activation (3).The proposal that IL-1 plays a major part in the erosive processes of chronic inflammation is based on a separate line of investigation. A substance isolated from synovial lining cultures and termed catabolin was found to promote cartilage breakdown (4). When purified to homogeneity, catabolin was shown to have properties identical to IL-1 (5). It is now known that IL-1 stimulates the release of metalloproteinases, such as stromelysin and collagenase, from synovial cells and chondrocytes in culture and that these enzymes degrade cartilage matrix (6). In these cultures, IL-1 also stimulates PGE2 production (7).We have now injected IL-1 into the knee joints or skin of New Zealand White rabbits and have measured inflammatory changes at intervals up to 3 days. Following intraarticular injection of IL-1, joint swelling, leukocyte accumulation, cartilage degradation, and icosanoid synthesis were measured. The responses induced by IL-1 were compared with changes seen in the joints of rabbits with antigen-induced arthritis (8) 1-14 days after antigen chal...
Among the nonsteroid antiinflammatory drugs there is generally a close correlation between the potency of their inhibition of arachidonate cyclooxygenase, and thus prostaglandin production, and their antiinflammatory activity.One anomaly in this generalization is that whereas aspirin and salicylate are equipotent as antiinflammatory agents, salicylate is less active than aspirin in inhibiting prostaglandin production in vitro. Using rats, we have now measured the concentrations of aspirin and salicylate in plasma and in inflammatory exudates after their oral administration and determined their effects on thromboxane B2 production in clotting blood and prostaglandin (PG) E2 concentrations in the exudates. We have also investigated the effects of both drugs, at concentrations achieved in the exudates, on PGE2 production by nonproliferative explants of acutely inflamed tissues. Aspirin is rapidly metabolized, resulting in peak concentrations of salicylate in the plasma and exudate that exceeded peak concentrations of aspirin by 30-to 50-fold. Furthermore, concentrations of aspirin rapidly declined, whereas high concentrations of salicylate persisted in the plasma and in the exudate for up to 6 hr after a single administration of aspirin. Both drugs reduced PGE2 concentrations in inflammatory exudates by 50-70%, but aspirin was considerably more potent than salicylate in inhibiting thromboxane B2 production in clotting blood. The concentration of salicylate found in inflammatory exudates 6 hr after the administration of aspirin was sufficient to reduce PGE2 production in explants by more than 50%. We conclude that the antiinflammatory action of both drugs depends on the inhibition of PGE2 synthesis by salicylate.The discovery that aspirin, indomethacin, and salicylate inhibit the synthesis of prostaglandins (1-3) provided the first comprehensive explanation of the mechanism of action of these drugs. Subsequent studies have shown that the broad group of nonsteroid antiinflammatory drugs inhibits arachidonate cyclooxygenase, the enzyme that converts arachidonic acid to prostaglandin endoperoxides (for review see ref. 4). However, anomalies exist in the potencies of these drugs with respect to their antiinflammatory activities and to their ability to inhibit cyclooxygenase; of particular interest has been the disparity between the potency of aspirin and salicylate in inhibiting cyclooxygenase. Aspirin and salicylate are equipotent as antiinflammatory agents, but aspirin is some 20 times more potent than salicylate in inhibiting an enzyme preparation from guinea pig lung in vitro (1). Furthermore, it has been reported that oral administration of aspirin (10 mg/kg) inhibited thromboxane (TX) production by rat platelets but 20 times this dose of salicylate had no effect (5). These findings led to speculation that the antiinflammatory activity of these drugs was not related to inhibition of prostaglandin (PG) synthesis (5, 6).We have now (i) measured the concentrations of aspirin and salicylate in plasma and inflam...
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