Characterization of the transduction pathway involved in c-fos and c-jun expression induced by Aggregatibacter actinomycetemcomitans lipopolysaccharides in human gingival fibroblasts

• Published in: International immunopharmacology 2008-11, Vol.8 (11), p.1513-1523
• Main Authors: Gutiérrez-Venegas, Gloria, Castillo-Alemán, Ramiro
• Format: Article
• Language: English
• Subjects: Aggregatibacter actinomycetemcomitans - immunology; Bacterial diseases; Biological and medical sciences; Cells, Cultured; Ent and stomatologic bacterial diseases; ERK 1/2; Facial bones, jaws, teeth, parodontium: diseases, semeiology; Fibroblasts - drug effects; Fibroblasts - immunology; Fibroblasts - metabolism; Fibroblasts - microbiology; Gingiva - drug effects; Gingiva - immunology; Gingiva - metabolism; Gingiva - microbiology; Human bacterial diseases; Humans; Infectious diseases; Inflammation; Lipopolysaccharide; Lipopolysaccharides - immunology; Lipopolysaccharides - isolation & purification; Lipopolysaccharides - pharmacology; Medical sciences; Non tumoral diseases; Otorhinolaryngology. Stomatology; p38; Periodontal disease; Periodontal Diseases - immunology; Periodontal Diseases - microbiology; Phospholipase C; Protein kinase A; Protein kinase C; Protein Kinase Inhibitors - pharmacology; Protein Kinases - drug effects; Protein Kinases - immunology; Protein Kinases - metabolism; Proto-Oncogene Proteins c-fos - immunology; Proto-Oncogene Proteins c-fos - metabolism; Proto-Oncogene Proteins c-jun - immunology; Proto-Oncogene Proteins c-jun - metabolism; Signal Transduction - drug effects; Signal Transduction - immunology; Tetradecanoylphorbol Acetate - analogs & derivatives; Tetradecanoylphorbol Acetate - pharmacology
• ISSN: 1567-5769; 1878-1705
• DOI: 10.1016/j.intimp.2008.06.007

Periodontal disease is an inflammatory disease caused by infection with oral bacteria that results in tooth exfoliation. Lipopolysaccharides (LPS) are a major component of the outer membrane of Gram-negative microorganisms and are involved in the inflammatory response. c-fos and c-jun are involved in pathological conditions such as inflammatory disorders. Inflammatory signaling cascades leading to c-fos activation in human gingival fibroblasts (HGFs) are not well characterized. Thus, we have investigated the kinase pathways involved in c-fos and c-jun activation induced by LPS in human gingival fibroblasts. LPS promoted a dose- and time-dependent increase in c-fos transcription. Phosphoinositide-phospholipase C inhibitor (U-73122), protein kinase A inhibitor (H89), MEK1 inhibitor (PD 98,059), p38 inhibitor (SB203580), and tyrosine kinase inhibitors (genistein and herbimycin) attenuated the LPS effect, while the PI-3 K inhibitor (Wortmannin) had no effect on LPS-induced c-fos transcription. Protein kinase C inhibitors (Ro 31-8220, calphostin C, staurosporine, and chelerythrine chloride) also inhibited LPS-induced c-fos transcription. However, long-term treatment (24 -h) with the PKC activator tetradecanoyl phorbol-13-acetate (PMA) had no significant effect on LPS-induced transcription in HGFs. We also found an increase in c-jun expression in HGF stimulated with LPS. In addition, experiments using pharmacological inhibitors of individual mitogen-activated protein kinases (MAPK) and of protein kinase C (PKC) revealed that p38, ERK 1/2, and PKC are involved in LPS-induced c-jun expression. Our results indicate that LPS-induced c-fos and c-jun expressions are mediated by two different signaling pathways: one through phosphoinositide-phospholipase C via an upstream protein tyrosine kinase, which activates PKC isoforms that are insensitive to phorbol stress, and the second through activation of protein kinase A (PKA). Both kinases regulate the phosphorylation of the extracellular signal-regulated kinase ERK 1/2 and p38.