Primary human articular chondrocytes, dedifferentiated chondrocytes, and synoviocytes exhibit differential responsiveness to interleukin‐4: Correlation with the expression pattern of the common receptor gamma chain

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Abstract
Interleukin (IL)‐4, which exhibits potent anti‐inflammatory activities, is of potential therapeutic value in destructive arthropathies. To further define the response of human joint cells to IL‐4, we analyzed the ability of this cytokine to modulate the effects of IL‐1β and growth factors. Freshly isolated chondrocytes, dedifferentiated chondrocytes, and synoviocytes were treated with IL‐4 before determination of nitric oxide (NO) and collagenase production in response to IL‐1β, or before proliferation assays in presence of IL‐1β, platelet‐derived growth factor (PDGF), or transforming growth factor (TGF)‐β. IL‐4 downregulated IL‐1β induced NO production in dedifferentiated chondrocytes and inhibited IL‐1β induced collagenase release, as well as IL‐1β and growth factor induced proliferation in dedifferentiated chondrocytes and synoviocytes. In contrast, IL‐4 had no effect in freshly isolated primary chondrocytes and in cartilage explants. The lack of response to IL‐4 in primary chondrocytes was associated with impaired signal transduction, as indicated by markedly decreased IL‐4 dependent tyrosine phosphorylation of signal transducer and activator of transcription (STAT)‐6. It also correlated with differences in the expression pattern of IL‐4 receptor (IL‐4R) subunits during chondrocyte dedifferentiation. Indeed, whereas the IL‐4Rα and IL‐13Rα′ subunits were expressed in all cell types, expression of the common receptor gamma chain was restricted to freshly isolated chondrocytes. In conclusion, IL‐4 downregulated IL‐1β‐induced catabolic events and cell proliferation in dedifferentiated chondrocytes and synoviocytes, but had no effects in freshly isolated chondrocytes. The difference in IL‐4 responsiveness between primary and dedifferentiated chondrocytes correlated with changes in proximal signaling events and in the expression pattern of IL‐4R subunits during cell dedifferentiation.

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