Biologic effects of an interleukin‐1 receptor antagonist protein on interleukin‐1–stimulated cartilage erosion and chondrocyte responsiveness

Abstract

Recombinant human interleukin-la (IL-la) and recombinant human IL-1P stimulate matrix proteoglycan degradation and inhibit glycosaminoglycan synthesis in bovine nasal cartilage explants. A 17-kd human recombinant IL-1 receptor antagonist protein (IRAP) caused a concentration-dependent (0.2-200 ng/ml) suppression of the effects of IL-la and IL-lP in cartilage organ cultures. IRAP inhibited the binding of radiolabeled IL-la to rabbit articular chondrocytes. Matrix metalloproteinase (collagenase, gelatinase, and stromelysin) and prostanoid production by IL-l-activated rabbit articular chondrocytes was also suppressed by IRAP. These results could have potential significance in the development of a new antiarthritis therapy based on an IRAP.Interleukin-1 (IL-1) is a 17-kd polypeptide that is produced by a variety of cells and is believed to play a major role in hoddefense and inflammation (1,2).Two forms of IL-1 ( a and p), which bind to the same receptor (2) and exert comparable effects on numerous target cells, have been identified (2). Although the role of IL-1 in physiologic events awaits clarification, the presence of IL-1 in arthritic joint fluid (1,2), together with the ability of this cytokine to induce cartilage degradation (2,3) and bone resorption (2), emphasizes the probable participation of IL-1 in the pathogenesis of rheumatic disease. Thus, inhibition of these and other deleterious activities of IL-1 might represent an effective therapy for inflammatory joint diseases.IL-1 receptor antagonists have been identified in the urine of patients with fever (4) and in culture media of growth factor-activated monocytes (5). An antagonist of IL-1 activity was purified from the culture supernatant of immune complex-activated monocytes (2). This protein inhibited IL-1 receptor binding and was termed IL-1 receptor antagonist (6,7). A human myelomonocytic cell line (U937)Aerived IL-1 receptor antagonist protein (IRAP) was recently purified, sequenced, cloned, and expressed (8). IRAP was shown to inhibit IL-I activity in vitro and in vivo (8).The purpose of the present study was to investigate the effects of IRAP on IL-l-elicited cartilage erosion and on matrix metalloproteinase (MMP) and prostaglandin E, (PGE,) production by IL-l-activated chondroc ytes. MATERIALS AND METHODSCartilage explant cultures. Methods for preparation of cartilage organ cultures and for quantitation of matrix degradation (glycosaminoglycan [GAG] release) and GAG synthesis (incorporation of 35S-sulfate into cartilage discs) have been described previously (3). Cartilage explants were cultured for 8 days in Dulbecco's modified Eagle's medium (DMEM) with 5% heat-inactivated fetal calf serum (FCS). Each experimental group was assayed in quintuplicate.Chondrocyte cultures. Confluent monolayer cultures of rabbit articular chondrocytes (RAC) were used throughout these studies. Monolayer cultures Arthritis and Rheumatism, Val. 34, No. 1 (January 1991)

Imbalance between interleukin-1 agonists and antagonists: relationship to severity of inflammatory bowel disease

“…Several mechanisms could explain the failure of the naturally occurring anti-inflammatory mediators to set a new balance. First, a large excess of IL-1Ra is required to block the binding of IL-1 to the IL-1 type I receptor [44]. It is generally thought that a 10-100-fold excess of IL-1Ra is required to achieve efficient antagonism.…”

Treatment of experimental equine osteoarthritis by in vivo delivery of the equine interleukin-1 receptor antagonist gene

“…[15][16][17][19][20][21][22][23][24][25][26][27] Furthermore, to circumvent the need for repeated protein administration, some of these studies utilized gene transfer to obtain sustained IL-1Ra levels. [15][16][17]19,20,25,27,28 However, the study presented here not only utilized a species with naturally occurring OA, but the IL-1Ra gene was expressed in the species from which it was obtained and is the first to use an autologous IL-1Ra gene in an adenoviral vector.…”

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

“…[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. 11,12 The results indicate that treatment with IL-1Ra lowers the levels of proteins involved in the acute phase of RA and the counts of swollen joints and, furthermore, may inhibit radiographic progression of the disease.…”