Actinobacillus actinomycetemcomitans lipopolysaccharide regulates matrix metalloproteinase, tissue inhibitors of matrix metalloproteinase, and plasminogen activator production by human gingival fibroblasts: A potential role in connective tissue destruction

Abstract

Fibroblasts, a major constituent of gingival connective tissue, can produce immunoregulatory cytokines and proteolytic enzymes that may contribute to tissue destruction. In this study, we evaluated the production of matrix metalloproteinases (MMPs), tissue inhibitors of MMPs (TIMPs), and plasminogen activators by gingival fibroblasts stimulated with lipopolysaccharides (LPS) produced by periodontopathogens, including Actinobacillus actinomycetemcomitans. In addition, changes in the expression and phosphorylation state of fibroblast intracellular signaling proteins induced by A. actinomycetemcomitans LPS were characterized using antibody microarrays. We showed that A. actinomycetemcomitans LPS induced the production of a 50 kDa plasminogen activator, MMP-2 and, to a lesser extent, MMP-3 by fibroblasts. The stimulation of fibroblasts with A. actinomycetemcomitans LPS also resulted in the overproduction of TIMP-1, but had no effect on the production of TIMP-2. Comparable responses were also obtained with Porphyromonas gingivalis and Fusobacterium nucleatum subsp. nucleatum LPS. The results of the microarray analyses showed that A. actinomycetemcomitans LPS induced changes in the phosphorylation state and expression of gingival fibroblast intracellular signaling proteins. More specifically, they suggested that A. actinomycetemcomitans LPS may induce both Jun N-terminus protein-serine kinases (JNK) and mitogen-activated protein-serine kinase p38 alpha (p38alpha MAPK) pathway activation, leading to increased activator protein-1 (AP-1) and nuclear factor kappa-B (NFkappaB) activities, which in turn can stimulate MMP-2, MMP-3, TIMP-1, and urokinase-type plasminogen activator (uPA) expression. This may contribute to periodontal connective tissue destruction.

Influence of Aging on Biological Properties of Periodontal Ligament Cells

“…In the present study, mRNA levels of TIMP-1 and -2 were also assessed, and the findings demonstrated suggest that aging stimulated TIMP-1 mRNA levels in PDLC, but had no significant effect on TIMP-2 mRNA levels. These observations are in line with the findings reported by Bodet et al [50] and may reflect an attempt to maintain periodontal tissue homeostasis as a consequence of the increased levels of MMP-2 and -8.…”

Tetracyclines and Chemically Modified Tetracycline-3 (CMT-3) Modulate Cytokine Secretion by Lipopolysaccharide-Stimulated Whole Blood

“…P. gingivalis LPS induces the secretion of inflammatory mediators and MMPs by macrophages and gingival fibroblasts [7][8][9]. In a recent study, we showed that stimulating human WB with P. gingivalis LPS causes a strong inflammatory response, with the production of pro-inflammatory cytokines and chemokines [10].…”

Beyond Good and Evil in the Oral Cavity: Insights into Host-Microbe Relationships Derived from Transcriptional Profiling of Gingival Cells

“…Furthermore, hsp60-induced epithelial cell migration may lead to local invasion of infected epithelium in some mucosal infections, or to increased cell invasion in infected tumors . Besides hsp60, the LPS from A. actinomycetemcomitans induces rapid p44 and p42 phosphorylation (ERK 1 and ERK 2, respectively) in human gingival fibroblasts (Gutierrez-Venegas et al 2006) and activates ERK, JNK, p38 and IκBα in these cells (Bodet et al 2007;Mochizuki et al 2004). It has been shown that the induction of IL-6 by IL-1β and A. actinomycetemcomitans LPS requires signaling through multiple MAPK pathways, including MKK-3-p38α ERK, JNK and p38 MAPK in mPDL cells (murine periodontal ligament cell line).…”