Independent effects of interleukin‐1 on proteoglycan breakdown, proteoglycan synthesis, and prostaglandin E₂ release from cartilage in organ culture

Abstract

Exposure of bovine nasal cartilage in culture to interleukin-1 (IL-1) leads to a time-and concentrationdependent stimulation of proteoglycan breakdown and prostaglandin E, (PGE,) release, and to inhibition of proteoglycan synthesis. The threshold levels of IL-1 required for initiating these effects were different, and IL-1 was 10 times more potent in inhibiting synthesis than in stimulating breakdown of proteoglycan. Kinetic studies indicated that the effects on proteoglycan metabolism occurred earlier (16-24 hours) than those for PGE, release (48 hours). Selective effects were observed with inhibitors. Nonsteroidal antiinflammatory drugs blocked PGE, production in response to IL-1, but had no effect on proteoglycan metabolism, and the antiarthritic drugs that blocked IL-1-stimulated breakdown augmented the inhibition of proteoglycan synthesis. We suggest that the effects of IL-1 on proteoglycan breakdown, proteoglycan synthesis, and PGE, release are mediated by independent post-receptor mechanisms.Interleukin-I (IL-I) is a monokine (1) that exhibits a number of immunologic effects (2-6) and modulates a variety of inflammatory functions relevant to rheumatic diseases, including the induction of fever (7), acute-phase proteins (8), and muscle proteolysis

Protection against collagen-induced arthritis by intramuscular gene therapy with an expression plasmid for the interleukin-1 receptor antagonist

“…[2][3][4][5] It is well known that IL-1 can stimulate monocytes, recruit inflammatory cells and induce secretion of factors that degrade cartilage. 28 In animal studies, systemic administration of IL-1 has been found to accelerate the development of CIA.…”

“…1 Although the causes of RA are not fully understood, various experimental and clinical studies suggest that proinflammatory cytokines, particularly interleukin-1 (IL-1) among others, have an important role in RA pathogenesis. [2][3][4][5] The IL-1 receptor antagonist (IL-1Ra) is a natural protein that competitively inhibits the binding of IL-1b and IL-1a to IL-1 receptor types I and II in humans and various animals, and improves the inflammatory symptoms of arthritis in experimental animal models. 1,[6][7][8][9][10] Several independent clinical trials have been completed in which the recombinant IL-1Ra protein has been administered for a long-term period to patients with RA.…”

Electro-gene therapy of collagen-induced arthritis by using an expression plasmid for the soluble p75 tumor necrosis factor receptor-Fc fusion protein

“…It has been reported that IL-1b and IL-12 each play an important role in the pathogenesis of arthritis. 3,[33][34][35][36] Therefore, it is likely that one of the possible mechanisms involved in the suppression of arthritis by sTNFR:Fc is the inhibition of TNF-a-induced production of IL-1b and IL-12. The inhibitory effect of sTNFR:Fc on the level of IL-12 also suggests that sTNFR:Fc may downregulate Th1 activity, since IL-12 is known to play a pivotal role in promoting the differentiation of Th1 responses and inducing IFNg production.…”

Modulation of hu/mu severe combined immunodeficient (SCID) mouse arthritis by local application of human recombinant IL-1β, IL-2 and IL-6

“…IL-1 induces a broad range of effects in RA and enhances thereby the inflammatory process and cartilage destruction in the joint [7][8][9][10][11][12][13][14][15]. Killar & Dunn showed that the development of collageninduced arthritis was faster and the disease more severe following additional administration of IL-1 [28].…”

“…IL-1 is one of the best investigated cytokines. It exhibits a potent catabolic action on cartilage [9] and decreases the synthesis of proteoglycans [10]. IL-1 stimulates the proliferation of osteoclasts and resorption of bone [11].…”