Development of selective tolerance to interleukin‐1β by human chondrocytes in vitro*

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Abstract
Interleukin‐1 induces release of NO and PGE2 and production of matrix degrading enzymes in chondrocytes. In osteoarthritis (OA), IL‐1 continually, or episodically, acts on chondrocytes in a paracrine and autocrine manner. Human chondrocytes in chondron pellet culture were treated chronically (up to 14 days) with IL‐1β. Chondrons from OA articular cartilage were cultured for 3 weeks before treatment with IL‐1β (0.05–10 ng/ml) for an additional 2 weeks. Spontaneous release of NO and IL‐1β declined over the pretreatment period. In response to IL‐1β (0.1 ng/ml), NO and PGE2 release was maximal on Day 2 or 3 and then declined to near basal level by Day 14. Synthesis was recovered by addition of 1 ng/ml IL‐1β on Day 11. Expression of inducible nitric oxide synthase (iNOS), detected by immunofluorescence, was elevated on Day 2 and declined through Day 14, which coordinated with the pattern of NO release. On the other hand, IL‐1β‐induced MMP‐13 synthesis was elevated on Day 3, declined on Day 5, and then increased again through Day 14. IL‐1β increased glucose consumption and lactate production throughout the treatment. IL‐1β stimulated proteoglycan degradation in the early days and inhibited proteoglycan synthesis through Day 14. Chondron pellet cultures from non‐OA cartilage released the same amount of NO but produced less PGE2 and MMP‐13 in response to IL‐1β than OA cultures. Like the OA, IL‐1β‐induced NO and PGE2 release decreased over time. In conclusion, with prolonged exposure to IL‐1β, human chondrocytes develop selective tolerance involving NO and PGE2 release but not MMP‐13 production, metabolic activity, or matrix metabolism.