The role of second messengers, prostaglandins and interleukin-6 in the regulation of chondrocyte metabolism by interleukin-1

Interleukin 1 (IL-1) is a powerful modulator of chondrocyte metabolism, and it is widely accepted that IL-1 contributes to the pathogenesis of the inflammatory arthritides. The purpose of these studies was to investigate the molecular mechanisms underlying the interleukin 1 (IL-1) response in chondrocytes. Significant differences were observed in the ability of chondrocytes to respond to IL-1 depending on the presence and absence of serum. Chondrocyte proteoglycan synthesis and nuclear transcription factor expression/activation were differentially affected by IL-1 depending on the presence or absence of serum. Specifically, chondrocyte proteoglycan synthesis was decreased by IL-1 in the presence of serum and increased by IL-1 in the absence of serum. Furthermore, IL-1 was able to enhance c-fos transcription and nuclear factor kappa beta (NF-kB) activation only in the presence of serum. These studies demonstrate that signal transduction pathways contributed by IL-1 and those contributed by other serum factors interact to produce a cellular response to IL-1 in chondrocytes. It also was demonstrated that IL-1 stimulates prostaglandin production, cAMP accumulation, and PKA activation in chondrocytes independently of the presence or absence of serum. Additionally, chondrocytes produced elevated levels of IL-6 in response to IL-1. Although there was no indication that IL-6 contributed to the degenerative responses associated with IL-1, prostaglandin synthesis was shown to contribute to IL-1 induction of interleukin 6 (IL-6) gene expression in chondrocytes. IL-1 did not induce chondrocytes to produce leukotrienes. However, when prostaglandin synthesis was inhibited, leukotrienes contributed to IL-1 induction of IL-6 expression indicating that arachidonic acid can shunt between the cyclooxygenase and lipoxygenase pathways. Furthermore, the contribution of eicosanoids to IL-1 induction of IL-6 was significantly greater in knee chondrocytes as compared to ankle chondrocytes. Additionally, it was demonstrated here for the first time, that ankle and knee chondrocytes which express the type I IL-1 receptor, express message for IL-1 type II receptor. These two forms of the IL-1 receptor in chondrocytes may interact to contribute intracellular signalling pathways in response to IL-1.