Background Studies suggest that interleukin-1 (IL-1) is the key mediator of arthritis and we have investigated the effect of IL-1 on cartilage degradation. We demonstrated that IL-1 inhibited proteoglycan (PG) synthesis via enhanced nitric oxide (NO) synthesis by chondrocytes. We also demonstrated that IL-1 increased intracellular Ca²⁺ ion concentration ([Ca²⁺]i) of chondrocytes. On the other hand, interleukin-4 (IL-4) is a T-cell derived 20 kDa glycoprotein and antagonise the cytokine mediated cartilage degradation.

Objectives We examined the effect of IL-4 on IL-1-enhanced NO synthesis in parallel with intracellular Ca levels and PG synthesis.

Methods Bovine articular chondrocytes were obtained. PG synthesis was measured with [35S] sulfate incorporation. NO levels were measured by use of an NO chemiluminescence analyzer. Ca²⁺ imaging was carried out with Fura2-AM loaded chondrocyte using the digital fluorescence-imaging system.

Results In the presence of IL-4, IL-1-enhanced NO release was completely abolished. IL-4 functions mainly as anti-inflammatory, as well as IL-10 and IL-13. To our knowledge, this is the first report demonstrating an inhibitory effect of IL-4 in NO release stimulated by IL-1. Alterations in [Ca²⁺]i provide a ubiquitous cell signalling system that mediates a variety of cellular process. IL-1 evoked an increase in the levels of [Ca²⁺]i, a response characterised by a steep onset and followed by a slower decline to preexisting values. IL-4 also abolished the IL-1-induced [Ca²⁺]i increase in the chondrocytes. We examined the effect of IL-4 on PG synthesis. Although IL-4 did not affect PG synthesis, IL-1-inhibited PG synthesis was reversed with the addition of IL-4. It is possible that IL-4 reversed the IL-1-inhibited PG synthesis through the inhibition of NO synthesis and [Ca²⁺]i increase.

Conclusion IL-4 plays a chondroprotecting effect antagonising with IL-1-inhibited PG synthesis.

References

1. Yeh LA, Augustine AJ, Lee P, Riviere LR, Sheldon A. Interleukin-4, an inhibitor of cartilage breakdown in bovine articular cartilage explants. J Rheumatol. 1995;22(9):1740–6

2. Fukuda K, Kumano F, Takayama M, Saito M, Otani K, Tanaka S. Zonal differences in nitric oxide synthesis by bovine chondrocytes exposed to interleukin-1. Inflamm Res. 1995;44(10):434–7