CD40 engagement modulates the production of matrix metalloproteinases by gingival fibroblasts

Chronic periodontitis is a destructive inflammatory disease linked with unb alanced production between matrix metalloproteinases (MMPs), such as inters titial collagenase (MMP-1) and stromelysin-1 (MMP-3) and their endogenous t issue inhibitors of MMPs (TIMPs). In addition to aberrant MMP-1 and MMP-3 e xpression, periodontal lesions are characterized by dense infiltrations of activated T lymphocytes which may interact with CD40-expressing gingival fi broblasts in the connective tissue via the CD40L-CD40 pathway. In this stud y we investigated whether CD40 cross-linking influenced MMP production by g ingival fibroblasts. Therefore, we analysed the CD40L-induced MMP productio n by these fibroblasts in the presence of cytokines that are increased in p eriodontal lesions, such as IL-1 beta, tumour necrosis factor-alpha (TNF-al pha) and interferon-gamma (IFN-gamma). We show that CD40 ligation on gingiv al fibroblasts resulted in a decrease of their MMP-1 and MMP-3 production, while MMP-2 and TIMP-1 production were unaffected as determined by Western blot. This down-regulatory effect of CD40 engagement on MMP-1 and MMP-3 pro duction by gingival fibroblasts was also present when MMP production was up -regulated by IL-1 beta and TNF-alpha or down-regulated by IFN-gamma. These results suggest that CD40 ligation on gingival fibroblasts leads to a rest raining of MMP-1 and MMP-3 production by gingival fibroblasts and thereby m ay be an important mechanism in the retardation of further periodontal tiss ue damage.