title: Characterization of the transduction pathway involved in c-fos and c-jun expression induced by Aggregatibacter actinomycetemcomitans lipopolysaccharides in human gingival fibroblasts.
abstract: 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.
authors.affiliation: Laboratorio de Bioquímica, División de Estudios de Posgrado e Investigación, Facultad de Odontología, Universidad Nacional Autónoma de México, Ciudad de México, México. gloria@fo.odonto.unam.mx
authors.forename: Gloria
authors.initials: G
authors.lastname: Gutiérrez-Venegas
authors.forename: Ramiro
authors.initials: R
authors.lastname: Castillo-Alemán
mesh_terms: D016976:Aggregatibacter actinomycetemcomitans / Q000276:immunology*; D002478:Cells, Cultured; D005347:Fibroblasts / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D005881:Gingiva / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology; D006801:Humans; D008070:Lipopolysaccharides / Q000276:immunology* / Q000302:isolation & purification / Q000494:pharmacology; D010510:Periodontal Diseases / Q000276:immunology* / Q000382:microbiology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011494:Protein Kinases / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000276:immunology / Q000378:metabolism*; D016755:Proto-Oncogene Proteins c-jun / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D013755:Tetradecanoylphorbol Acetate / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D008070:Lipopolysaccharides; D047428:Protein Kinase Inhibitors; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; C020922:4-O-methyl-12-O-tetradecanoylphorbol 13-acetate; D011494:Protein Kinases; D013755:Tetradecanoylphorbol Acetate