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.
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-1beta 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-1beta, or before proliferation assays in presence of IL-1beta, platelet-derived growth factor (PDGF), or transforming growth factor (TGF)-beta. IL-4 downregulated IL-1beta induced NO production in dedifferentiated chondrocytes and inhibited IL-1beta induced collagenase release, as well as IL-1beta 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-4Ralpha and IL-13Ralpha' 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-1beta-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.
Division of Rheumatology, Department of Internal Medicine, University Hospital, Geneva, Switzerland.
Jérôme
J
Guicheux
Gaby
G
Palmer
Biserka
B
Relic
Françoise
F
Mezin
Joseph
J
Caverzasio
Pierre
P
Apostolides
Jean-François
JF
Gauchat
Cem
C
Gabay
Pierre-André
PA
Guerne
D002358:Cartilage, Articular / Q000166:cytology*; D002454:Cell Differentiation / Q000502:physiology; D002455:Cell Division / Q000187:drug effects; D019902:Chondrocytes / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D017364:Collagenases / Q000378:metabolism; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology; D015847:Interleukin-4 / Q000494:pharmacology*; D009569:Nitric Oxide / Q000096:biosynthesis; D010766:Phosphorylation / Q000187:drug effects; D020033:Protein Isoforms / Q000378:metabolism; D019948:Receptors, Interleukin-4 / Q000378:metabolism*; D050800:STAT6 Transcription Factor; D013583:Synovial Membrane / Q000166:cytology* / Q000187:drug effects*; D015534:Trans-Activators / Q000378:metabolism
D007375:Interleukin-1; D020033:Protein Isoforms; D019948:Receptors, Interleukin-4; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; D015534:Trans-Activators; D015847:Interleukin-4; D009569:Nitric Oxide; D017364:Collagenases