Induction of Keratinocyte Growth Factor 1 Expression by Lipopolysaccharide Is Regulated by CD-14 and Toll-Like Receptors 2 and 4

Abstract

Periodontal disease is a chronic inflammatory condition that is associated with increased concentrations of gram-negative pathogenic bacteria and epithelial cell proliferation. Regulation of this proliferation is poorly understood but is most likely controlled by locally expressed growth factors. Keratinocyte growth factor 1, an epithelium-specific growth factor, is expressed by gingival fibroblasts, and its expression is regulated in a concentration-dependent manner by lipopolysaccharide. In this study, induction of keratinocyte growth factor 1 protein expression was dependent on gingival fibroblast expression of membrane CD14 (mCD14) and Toll-like receptors 2 and 4. Lipopolysaccharides from Escherichia coli and Porphyromonas gingivalis induced membrane expression of CD14 at 1, 3, and 24 h. Specifically, lipopolysaccharide induced low mCD14 expression gingival fibroblasts to express mCD14 at a level consistent with that of high mCD14 expression cells. Functional studies with specific blocking antibodies for CD14 and Toll-like receptors 2 and 4 implicated all of these molecules in signal transduction. The rapid decrease in cell membrane expression of Toll-like receptors 2 and 4 after treatment with lipopolysaccharide was consistent with receptor internalization, and blocking of either of these receptors completely inhibited keratinocyte growth factor 1 protein expression. The transcription factors AP-1 and NF-B were involved in lipopolysaccharide induction of keratinocyte growth factor 1 mRNA and protein expression. These results suggest that lipopolysaccharide may induce proliferation of periodontal epithelial cells by upregulating keratinocyte growth factor 1 expression via the CD14 and Toll-like receptor signaling pathway.

Membrane-Anchored CD14 Is Important for Induction of Interleukin-8 by Lipopolysaccharide and Peptidoglycan in Uroepithelial Cells

“…It had generally been thought that fibroblasts, epithelial cells, and endothelial cells do not express the membrane-anchored form (mCD14) and that complexes containing LPS and serum sCD14 interact with TLR4-MD-2 at the cell surface (4,20,26). However, recent reports suggest that mCD14 is indeed present in several fibroblast and endothelial cell lines (12,21,25).…”

Porphyromonas gingivalis Lipopolysaccharide Contains Multiple Lipid A Species That Functionally Interact with Both Toll-Like Receptors 2 and 4

“…In fact, this LPS is a natural antagonist for the human endothelial E-selectin and IL-8 responses to E. coli LPS and other oral bacteria (11) and has recently been reported to be a TLR4 antagonist in some cell types (8,10,68). Furthermore, although several reports have demonstrated that this LPS utilizes TLR2 instead of TLR4 for host cell activation (5,26,37), it has also been reported to engage TLR4 (42,57) to facilitate gingival fibroblast activation through mCD14 (46,62).…”

Heat shock protein concentrations in chronic generalized periodontitis of elderly patients

“…Chemokines attract lympho cytes and macrophages to the site of inflammation, which causes the formation of dental granulomas. Proinflammatory cytokines activate osteoclasts, which destroy interalveolar walls and cause the destruction of the teeth and jaws [18,19].…”