Effects of IL-6 and its soluble receptor on proteoglycan synthesis and NO release by human articular chondrocytes: comparison with IL-1. Modulation by dexamethasone.
Contradictory results have been reported on the effects and role of IL-6 on proteoglycan (PG) synthesis. Having shown recently that in vitro IL-6 depends on the presence of soluble IL-6 receptor alpha (sIL-6Ralpha) to fully exert its effects on chondrocytes, we conducted the present study to analyse the effects of IL-6 on PG synthesis by human articular chondrocytes in the presence of sIL-6Ralpha. PG synthesis was quantified by specific ELISA using a monoclonal antibody (MAB) raised against the keratan sulphate region of PG as a capture antibody, and a MAB to the acid binding region as a detector. It proved specific for PG from primary (differentiated) chondrocytes. In the absence of sIL-6Ralpha, IL-6 had a slight inhibitory effect on PG synthesis by articular chondrocytes. sIL-6Ralpha alone also had slight but consistent inhibitory effects. When adding sIL-6Ralpha at concentrations of 50 ng/ml corresponding to levels found in synovial fluid, the effects of IL-6 increased consistently. However, even at optimal concentrations (30-100 ng/ml of IL-6sR per 100 ng/ml of IL-6), maximal inhibition (48%) did not equal the degree of inhibition achieved by IL-1 at 1 ng/ml (66%). Similar effects, although slightly weaker, were observed on osteoarthritic cells. Dexamethasone, over a wide range of concentrations, markedly enhanced proteoglycan synthesis and completely reversed the downregulatory effects of IL-1 and IL-6 + sIL-6Ralpha. The effects of IL-1 were partially inhibited by an anti-IL-6 antibody. Finally, unlike IL-1, IL-6 + sIL-6Ralpha only weakly stimulated nitric oxide (NO) synthesis. In conclusion, sIL-6Ralpha potentiates the inhibitory effect of IL-6 on PG synthesis by articular chondrocytes, but the overall effect of IL-6 + IL-6sR is moderate compared to the effects of IL-1.
Guerne
P A
PA
Division of Rheumatology, Hôpital Cantonal Universitaire, Geneva, Switzerland. pierre-andre.guerne@medecine.unige.ch
Desgeorges
A
A
Jaspar
J M
JM
Relic
B
B
Peter
R
R
Hoffmeyer
P
P
Dayer
J M
JM
D000818:Animals; D002358:Cartilage, Articular / Q000166:cytology / Q000378:metabolism; D019902:Chondrocytes / Q000187:drug effects / Q000378:metabolism*; D003907:Dexamethasone / Q000378:metabolism* / Q000494:pharmacology; D005938:Glucocorticoids / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D007375:Interleukin-1 / Q000378:metabolism* / Q000494:pharmacology; D015850:Interleukin-6 / Q000378:metabolism* / Q000494:pharmacology; D051379:Mice; D009569:Nitric Oxide / Q000378:metabolism*; D010003:Osteoarthritis; D011509:Proteoglycans / Q000096:biosynthesis*; D019947:Receptors, Interleukin-6 / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D005938:Glucocorticoids; D007375:Interleukin-1; D015850:Interleukin-6; D011509:Proteoglycans; D019947:Receptors, Interleukin-6; D009569:Nitric Oxide; D003907:Dexamethasone