Interleukin-4, an inhibitor of cartilage breakdown in bovine articular cartilage explants.
OBJECTIVE
To determine the ability of interleukin-4 (IL-4) to inhibit the degradation of proteoglycan in bovine articular cartilage explants stimulated by human interleukin-1 (IL-1 alpha), tumor necrosis factor (TNF-alpha), a combination of TNF-alpha and IL-1 alpha, and lipopolysaccharide (LPS).


METHODS
35SO4 radiolabelled bovine radiocarpal cartilage explants were treated with IL-1 alpha, TNF-alpha, TNF-alpha plus IL-1 alpha, or LPS, plus various concentrations of IL-4 for 72 h. Proteoglycan released to the media was analyzed by scintillation counting and composite gel electrophoresis. Media samples were also analyzed by Western immunoblotting for metalloproteinases and TIMP.


RESULTS
IL-4 significantly reduced the cartilage proteoglycan degradation induced by IL-1 alpha, TNF-alpha, TNF-alpha plus IL-1 alpha, or LPS (50% inhibitory concentration, IC50 for IL-4 ranged from about 15 to 50 ng/ml). Western blotting showed that media stromelysin levels were increased by IL-1 alpha, TNF-alpha, and LPS, but that IL-4 had no observable effect. Composite gel electrophoresis demonstrated quantitative and qualitative differences in proteoglycan degradation after IL-4 treatment.


CONCLUSIONS
IL-4 has a potent inhibitory effect on cartilage degradation after stimulation with IL-1 alpha, TNF-alpha, TNF-alpha plus IL-1 alpha, or LPS. These results suggest that IL-4 should be investigated further for therapeutic value as a chondroprotective agent for the treatment of arthritis.
Department of Enzyme Biochemistry, OsteoArthritis Sciences, Inc., Cambridge, MA 02139, USA.
L A
LA
Yeh
A J
AJ
Augustine
P
P
Lee
L R
LR
Riviere
A
A
Sheldon
D000818:Animals; D002358:Cartilage, Articular / Q000187:drug effects* / Q000378:metabolism; D002417:Cattle; D007375:Interleukin-1 / Q000494:pharmacology; D015847:Interleukin-4 / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D011509:Proteoglycans / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D007375:Interleukin-1; D008070:Lipopolysaccharides; D011509:Proteoglycans; D014409:Tumor Necrosis Factor-alpha; D015847:Interleukin-4