TGF-β dampens IL-6 signaling in articular chondrocytes by decreasing IL-6 receptor expression
In: Osteoarthritis and Cartilage, Jg. 27 (2019-08-01), S. 1197-1207
Online
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Summary Objective Transforming growth factor-β (TGF-β) is an important homeostatic regulator of cartilage. In contrast, interleukin-6 (IL-6) is a pro-inflammatory cytokine implicated in cartilage degeneration. Cross-talk between TGF-β and IL-6 is reported in tissues other than articular cartilage. Here, we investigated regulation of IL-6 signaling by TGF-β in articular chondrocytes. Design Human primary chondrocytes and the human G6 chondrocyte cell line were stimulated with TGF-β1 or interleukin-1β (IL-1β). Expression of IL-6 and IL-6 receptor (IL-6R) was determined on mRNA and protein level. TGF-β regulation of IL-6 signaling via phosho-STAT3 (p-STAT3) was determined using Western blot, in presence of inhibitors for IL-6R, and Janus kinase(JAK)- and activin receptor-like kinase ALK)5 kinase activity. Furthermore, induction of STAT3-responsive genes was used as a read-out for IL-6 induced gene expression. Results TGF-β1 increased IL-6 mRNA and protein expression in both G6 and primary chondrocytes. Moreover, TGF-β1 stimulation clearly induced p-STAT3), which was abolished by inhibition of either IL-6R, JAK- or ALK5 kinase activity. However, TGF-β1 did not increase expression of the STAT3-responsive gene SOCS3 and pre-treatment with TGF-β1 even inhibited induction of p-STAT3 and SOCS3 by rhIL-6. Interestingly, TGF-β1 potently decreased IL-6R expression. In contrast, IL-1β did increase IL-6 levels, but did not affect IL-6R expression. Finally, addition of recombinant IL-6R abolished the inhibitory effect of TGF-β1 on IL-6-induced p-STAT3 and downstream SOCS3, BCL3, SAA1 and MMP1 expression. Conclusions In this study we show that TGF-β decreases IL-6R expression, thereby dampening IL-6 signaling in chondrocytes. This reveals a novel effect of TGF-β, possibly important to restrict pro-inflammatory IL-6 effects to preserve cartilage homeostasis.
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TGF-β dampens IL-6 signaling in articular chondrocytes by decreasing IL-6 receptor expression
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Autor/in / Beteiligte Person: | H.M. van Beuningen ; F.A.J. van de Loo ; A. van Caam ; E.N. Blaney Davidson ; Koenders, Marije I. ; P.M. van der Kraan ; Wiegertjes, R. ; P.L.E.M. van Lent |
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Zeitschrift: | Osteoarthritis and Cartilage, Jg. 27 (2019-08-01), S. 1197-1207 |
Veröffentlichung: | Elsevier BV, 2019 |
Medientyp: | unknown |
ISSN: | 1063-4584 (print) ; 1197-1207 (print) |
DOI: | 10.1016/j.joca.2019.04.014 |
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