INTRODUCTION M atrix metalloproteinases (MMPs) are important mediators of connective tissue destruction in periodontitis, including MMP-1, -3, -8, and -9 (Birkedal-Hansen et al., 1993). Macrophages and lymphocytes are locally activated to produce pro-inflammatory interleukin-1 (IL-1), tumor necrosis factor- (TNF-), and IL-17 (Yao et al., 1995; Jovanovic et al., 1998), which are associated with a persistent over-expression of many MMPs (Liacini et al., 2005). Since fibroblasts are the predominant cells in gingival connective tissue, they likely participate in gingival pathology (Bronson et al., 1989; Konttinen et al., 2000). MMP-1 can initiate extracellular matrix destruction and cooperates with other MMPs in collagen degradation (Woessner, 1991). It accounts for most of the collagenase activity expressed by cultured gingival fibroblasts (Sakaki et al., 2004). Increased MMP-1 mRNA expression, together with that of MMP-3, has been demonstrated in periodontitis (Kubota et al., 1996). MMP-1 and MMP-3 effectively degrade numerous extracellular matrix substrates, including collagens and proteoglycans. MMP-3 has the capacity to activate pro-MMP-1, pro-MMP-8, and pro-MMP-9 in activation cascades (Sorsa et al. , 1990; Suzuki et al. , 1990; Ogata et al. , 1992). Increased MMP-1 and MMP-3 levels have been reported in gingival fibroblasts after stimulation with IL-1 and TNF- (Domeij et al., 2002). Thus, MMP-1 and MMP-3 in periodontitis appear to be locally produced and released in gingival tissue by activated fibroblasts (Ingman et al., 1994). Increased mRNA expression for MMP-8 (Tonetti et al. , 1993) and MMP-9 (Mäkelä et al., 1994) has also been reported in inflamed human gingiva. MMP-8 and MMP-9 mainly derive from polymorphonuclear leukocytes (Birkedal-Hansen et al. , 1993), but are also synthesized by fibroblasts in chronic inflammation (Unemori et al., 1991). MMP-8 is the main collagenase in inflamed gingival crevicular fluid (Sorsa et al., 1988), and its IL-1-mediated regulation may contribute to severe periodontitis (Abe et al. , 2001). The overall expression of MMP-9 is also increased in periodontitis (Birkedal-Hansen et al., 1993). IL-6 is important in T-cell activation and proliferation and acts synergistically with IL-1 (Ishimi et al., 1990), whereas IL-8 is the major chemoattractant for polymorphonuclear leukocytes (Baggiolini et al., 1994). IL-1 and TNF- are the major inducers of IL-6 and IL-8, and, in this respect, IL-17 shows a synergistic effect with IL-1 and TNF- (Katz et al., 2001). IL-17 is a pro-inflammatory cytokine produced mainly by activated T-cells (Yao et al., 1995). IL-17 induces production of IL-6 and IL-8 in rheumatoid synovial fibroblasts (Hwang et al., 2004) and IL-6 in gingival fibroblasts (Takahashi et al., 2005). In addition, IL-17 enhances the effects of IL- and TNF- on the synthesis of IL-6 and IL-8 in skin and synovial fibroblasts (Chabaud et al., 1998; Katz et al., 2001). We hypothesized that IL-17 plays an important role in the induction of some of the key pro- inflammatory cytokines produced and released by gingival fibroblast and peripheral blood-derived monocytes/macrophages. Since these cytokines are ABSTRACT Periodontitis is characterized by periodontal tissue destruction. Since interleukin-17 (IL-17) has been reported to up-regulate IL-1 and tumor necrosis factor-alpha (TNF-), it was hypothesized that it is increased in periodontitis and up-regulates these cytokines and tissue-destructive matrix metalloproteinases (MMP) in local migrant and resident cells. Immunocytochemistry disclosed elevated IL-1 , TNF- , and IL-17 levels in periodontitis. These cytokines induced proMMP-1 and especially MMP-3 in gingival fibroblasts, whereas MMP-8 and MMP-9 were not induced. IL-17 was less potent as a direct MMP inducer than IL-1 and TNF-, but it induced IL-1 and TNF- production from macrophages, and IL-6 and IL-8 from gingival fibroblasts. In accordance with these findings, immunocytochemistry disclosed that MMP-1 and MMP-3 were increased in periodontitis. Gingival fibroblasts may play an important role in tissue destruction in periodontitis via cytokine-inducible MMP-1 and MMP-3 production, in which IL-17 plays a role as a key regulatory cytokine. KEY WORDS: IL-1 , TNF- , IL-17, MMP, periodontitis. Received March 24, 2006; Last revision November 20, 2006; Accepted November 24, 2006 MMPs, IL-1, and TNF are Regulated by IL-17 in Periodontitis A. Beklen 1,2,3 , M. Ainola 2 , M. Hukkanen 2,4 , C. Gürgan 5 , T. Sorsa 6 , and Y.T. Konttinen 1,4,7 * 1 Department of Medicine/Invärtes medicin, Helsinki University Central Hospital, Helsinki, Finland; 2 Institute of Biomedicine/Anatomy, University of Helsinki, Finland; 3 Medico-social Centre, Dental Clinic, Bogazici University, Istanbul, Turkey; 4 ORTON Orthopaedic Hospital of the Invalid Foundation, Helsinki, Finland; 5 Department of Periodontology, Faculty of Dentistry, Ankara University, Turkey; 6 Institute of Dentistry, University of Helsinki, Dept. of Oral and Maxillofacial Diseases, Helsinki University Central Hospital, Finland; 7 COXA Hospital for Joint Replacement, Tampere, Finland; *corresponding author, yrjo.konttinen@helsinki.fi, Biomedicum Helsinki, PO Box 700 (Haartmaninkatu 8), FI-00029 HUS-Finland J Dent Res 86(4):347-351, 2007 RESEARCH REPORTS Biological 347