The effects of cytokines on metalloproteinase inhibitors (TIMP) and collagenase production by human chondrocytes and TIMP production by synovial cells and endothelial cells

Abstract

SUMMARY It has been suggested that IL-1 produces cartilage matrix degradation by metalloproteinases such as collagenase, and that such degradation is regulated by metalloproteinase inhibitors (TIMP). Therefore, the balance between collagenase and TIMP is an important factor for tissue destruction in inflammatory joints. In the present study the effects of cytokines on collagenase and TIMP production in chondrocytes as welt as the effects of cytokines on TIMP production in connective tissue cells were studied. IL-Iβ inhibited TIMP production in endothelial cells while enhancing TIMP production in synovial cells and chondrocytes. In addition, tumour necrosis factor-alpha (TNF-α) significantly inhibited and IL-6 significantly enhanced TIMP production in endothelial cells, synovial cells and chondrocytes. In the chondrocyte supernatant, collagenase activity/TIMP ratio was significantly elevated by the addition of either IL-lβ or TNF-α to the cells, whereas the ratio was significantly decreased by IL-6. These results suggest that the cytokine effects on TIMP production are different among the different cell types, and that either IL-lβ or TNF-α induce cartilage matrix degradation by disrupting the collagenase/TIMP balance, while, on the other hand, IL-6 protects the tissue through an opposite effect.