Development of selective tolerance to interleukin-1beta by human chondrocytes in vitro.
Interleukin-1 induces release of NO and PGE(2) and production of matrix degrading enzymes in chondrocytes. In osteoarthritis (OA), IL-1 continually, or episodically, acts on chondrocytes in a paracrine and autocrine manner. Human chondrocytes in chondron pellet culture were treated chronically (up to 14 days) with IL-1beta. Chondrons from OA articular cartilage were cultured for 3 weeks before treatment with IL-1beta (0.05-10 ng/ml) for an additional 2 weeks. Spontaneous release of NO and IL-1beta declined over the pretreatment period. In response to IL-1beta (0.1 ng/ml), NO and PGE(2) release was maximal on Day 2 or 3 and then declined to near basal level by Day 14. Synthesis was recovered by addition of 1 ng/ml IL-1beta on Day 11. Expression of inducible nitric oxide synthase (iNOS), detected by immunofluorescence, was elevated on Day 2 and declined through Day 14, which coordinated with the pattern of NO release. On the other hand, IL-1beta-induced MMP-13 synthesis was elevated on Day 3, declined on Day 5, and then increased again through Day 14. IL-1beta increased glucose consumption and lactate production throughout the treatment. IL-1beta stimulated proteoglycan degradation in the early days and inhibited proteoglycan synthesis through Day 14. Chondron pellet cultures from non-OA cartilage released the same amount of NO but produced less PGE(2) and MMP-13 in response to IL-1beta than OA cultures. Like the OA, IL-1beta-induced NO and PGE(2) release decreased over time. In conclusion, with prolonged exposure to IL-1beta, human chondrocytes develop selective tolerance involving NO and PGE(2) release but not MMP-13 production, metabolic activity, or matrix metabolism.
Thurston Arthritis Research Center and Department of Orthopedics, University of North Carolina, Chapel Hill, North Carolina 27599, USA. GML@med.unc.edu
Greta M
GM
Lee
Marianne E
ME
Tioran
Marilyn
M
Jansen
Ronald D
RD
Graff
Scott S
SS
Kelley
Peiyuan
P
Lin
D000368:Aged; D002478:Cells, Cultured; D019902:Chondrocytes / Q000187:drug effects* / Q000378:metabolism; D017364:Collagenases / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007375:Interleukin-1 / Q000378:metabolism / Q000494:pharmacology*; D019344:Lactic Acid / Q000096:biosynthesis; D053509:Matrix Metalloproteinase 13; D008875:Middle Aged; D009569:Nitric Oxide / Q000378:metabolism; D011509:Proteoglycans / Q000378:metabolism; D013997:Time Factors
D007375:Interleukin-1; D011509:Proteoglycans; D009569:Nitric Oxide; D019344:Lactic Acid; D017364:Collagenases; C507079:MMP13 protein, human; D053509:Matrix Metalloproteinase 13; D005947:Glucose; D015232:Dinoprostone