Objective. To compare the responses of chondrocytes from superficial and deep layers of normal human articular cartilage to interleukin-1 (IL-1) and IL-1 receptor antagonist protein (IRAP), and to evaluate the binding sites for IL-1 on these cells.Methods. Cartilage and chondrocytes from superficial and deeper layers of human femoral condyles were cultured with and without IL-1 in the presence and absence of IRAP. The effect of these agents on %-proteoglycan synthesis and catabolism and production of stromelysin and tissue inhibitor of metalloproteinases 1 (TIMP-1) were measured by biochemical and immunologic assays. Receptor binding was evaluated using '251-labeled IL-1.Results. IL-1 induced more severe inhibition of proteoglycan synthesis and a lower ratio of secreted TIMP-kstromelysin in chondrocytes from superficial cartilage than those from deeper cartilage. IRAP blocked responses to IL-1 more effectively in chondro- Submitted for publication April 10, 1995; accepted in revised form September 22, 1995.cytes from deep cartilage than those from superficial cartilage. Chondrocytes from the articular surface showed approximately twice the number of high-mity binding sites for IL-1 as did cells from deep cartilage.Conclusion. Chondmytes from the surface of articular cartilage show a greater vulnerability to the harmful effects of IL-1 and are less responsive to the potential therapeutic effects of IRAP than cells in the deeper layers of the tissue.Treatment of cartilage tissue in vitro with IL-1 (1,2) or injection of IL-1 into the synovial cavity (3,4) results in inhibition of synthesis of proteoglycans (PGs) (5-9), enhanced production of prostaglandin E2 (PGE,) (10) and metalloproteinases (1 l), and excessive catabolism of PGs. Together these conditions contribute to loss of cartilage matrix and inadequate tissue repair. Based on experimental results and on the finding of IL-1, PG fragments, and proteolytic enzymes in inflamed joints (12)(13)(14), it is widely accepted that IL-1 plays an important role in cartilage erosion in inflammatory joint diseases. Because PG synthesis is usually upregulated during the early stages of osteoarthritis (15), IL-1 has been given little attention as a potential mediator of early metabolic changes in articular cartilage. In patients, on the other hand, especially during the inflammatory episodes which almost always develop at late stages of the disease, IL-1 appears to play a significant role in suppressing the synthesis and repair mechanism (16). IL-1 a and IL-Ip, the 2 agonist isoforms of 1L-1 (17-21), bind to specific cell-membrane receptors and set in motion complex signal transduction pathways which are not yet fully understood (22). The human recombinant form of IL-1 receptor antagonist protein also binds to the same receptors, but since it fails to initiate signal transduction or elicit biological responses, it blocks cellular ARTICULAR SURFACE SUSCEPTIBILITY TO IL-1 479 responses to IL-1 (23) and acts as a pure antagonist (24)(25)(26)(27)(28).Two structurally related c...