The role of soluble interleukin (IL)-6 receptor in mediating the effects of IL-6 on matrix metalloproteinase-1 and tissue inhibitor of metalloproteinase-1 expression by gingival fibroblasts

Background: Interleukin-6 (IL-6) is a multifunctional cytokine thought to play a role in the tissue destruction that characterizes periodontal disease. IL-6 exerts its cellular effects through a cell-surface receptor which also exists in a soluble form (sIL-6r). This study investigated the effects of IL-6 on matrix metalloproteinase (MMP)-1 activity in gingival fibroblast cultures, specifically determining the role of the sIL-6r in mediating these actions. Methods: Fibroblasts were grown to confluence, washed in Hank's balanced saline solution (HBSS), and then cultured for 72 hours in serum-free medium supplemented with 0.2% bovine serum albumin, 1 mug/ml Escherichia coli LPS and containing various combinations of IL-6 and its soluble receptor over the concentration range 0 to 1,000 ng/ml. MMP-1 and tissue inhibitor of MMP (TIMP)-1 protein levels in the conditioned medium were assessed by enzyme-linked immunosorbent assay (ELISA) and collagenolytic activity determined using a H-3-acetylated type I collagen degradation assay. Results: Results indicated that the addition of IL-6 alone to cultures, over the concentration range 0 to 1,000 ng/ml, had no significant effect on MMP-1 protein expression. However, addition of IL-6 in combination with its soluble receptor resulted in a statistically significant, dose-dependent upregulation in MMP-1 expression. The IL-6/sIL-6r combination also induced a significant increase in collagenolytic activity in cultures. IL-6 and sIL-6r, either alone or in combination, had no marked effect on TIMP expression or cell growth. Conclusions: These data strongly suggest that future clinical studies investigating the role of IL-6 in periodontal disease must also determine the levels of sIL-6r within the periodontal tissues.