Porphyromonas gingivalisFimbria-Dependent Activation of Inflammatory Genes in Human Aortic Endothelial Cells

Abstract

Epidemiological and pathological studies have suggested that infection with the oral pathogen Porphyromonas gingivalis can potentiate atherosclerosis and human coronary heart disease. Furthermore, infection with invasive, but not noninvasive P. gingivalis has been demonstrated to accelerate atherosclerosis in apolipoprotein E-deficient (ApoE(-/-)) mice and to accelerate local inflammatory responses in aortic tissue. In the present study, using high-density oligonucleotide microarrays, we have defined the gene expression profile of human aortic endothelial cells (HAEC) after infection with invasive and noninvasive P. gingivalis. After infection of HAEC with invasive P. gingivalis strain 381, we observed the upregulation of 68 genes. Genes coding for the cytokines Gro2 and Gro3; the adhesion molecules intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule (VCAM)-1, and ELAM-1 (E-selectin); the chemokine interleukin-8 (IL-8); and the proinflammatory molecules IL-6 and cyclooxygenase-2 were among the most highly upregulated genes in P. gingivalis 381-infected HAEC compared to uninfected HAEC control. Increased mRNA levels for signaling molecules, transcriptional regulators, and cell surface receptors were also observed. Of note, only 4 of these 68 genes were also upregulated in HAEC infected with the noninvasive P. gingivalis fimA mutant. Reverse transcription-PCR, enzyme-linked immunosorbent assay, and fluorescence-activated cell sorting analysis confirmed the expression of ICAM-1, VCAM-1, E-/P-selectins, IL-6, and IL-8 in HAEC infected with invasive P. gingivalis. We also demonstrated that increased expression of ICAM-1 and VCAM-1 in aortic tissue of ApoE(-/-) mice orally challenged with invasive P. gingivalis but not with the noninvasive P. gingivalis fimA mutant by immunohistochemical analysis. Taken together, these results demonstrate that P. gingivalis fimbria-mediated invasion upregulates inflammatory gene expression in HAEC and in aortic tissue and indicates that invasive P. gingivalis infection accelerates inflammatory responses directly in the aorta.

Is Porphyromonas gingivalis Cell Invasion Required for Atherogenesis? Pharmacotherapeutic Implications

“…The reduced cytokine levels in the DPG3-challenged group support several other in vitro studies that have shown that invasive P. gingivalis can induce inflammatory cytokines IL-1␣, IL-1␤, IL-6, and TNF-␣ in gingival fibroblasts, epithelial cells, and macrophages (39 -41). Finally, previous findings indicating that FimA lacking DPG3 is unable to properly produce adhesion molecules involved in cell invasion (34) and only able to up-regulate 4 of 68 up-regulated inflammatory genes by wild-type P. gingivalis in human aortic endothelial cells also suggest a correlation between FimA-dependent cell invasiveness and the pathogenesis of cardiovascular disease (13). Therefore, in addition to the invasion deficiency, DPG3 lacks FimA, a known potent TLR2 ligand, and pathogenicity may be reduced to only LPS (36 -38, 40).…”

“…Porphyromonas gingivalis, which has been strongly associated with adult periodontitis, is a Gram-negative, nonmotile, obligate anaerobe that can invade and infect epithelium, endothelium, and vascular smooth muscle cells (6 -9) and appears to alter endothelial function (10). The capacity for invasion and the subsequent inflammatory responses is in part mediated by fimbriae (11)(12)(13), and the virulence of P. gingivalis may vary among individual strains depending on which one of the five major types of FimA gene they possess (14).…”

Gingipain-dependent interactions with the host are important for survival of Porphyromonas gingivalis

“…The recent findings that fimbriae from P. gingivalis modulated both pro-apoptotic and antiapoptotic genes in human aortic endothelial cells (36) and in gingival fibroblasts (211) confirmed that P. gingivalis could induce either apoptosis or resistance to apoptosis. It appears that the pathway that prevails in a given cell type depends on the balance of cell death and survival modulators that are present.…”

“…Furthermore, there is evidence that P. gingivalis infection may initiate divergent survival and death pathways (36). P. gingivalis fimbriae inhibited growth factor deprivation-induced apoptosis via ERK-dependent expression of p21 in a human monocytic cell line (153).…”

Mechanisms of Periodontitis - Induced Atherosclerosis

“…[21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38] PG�s fimbriae secretes protein, called gp130, [83] which facilitate PG to invade EC and trigger celluler immune response. [84] The host will secrete TNF, [85] IL-1, IL-6, IL-10, and IL-12 [86][87][88] by TLR�s stimulation. [26,85,[88][89][90] TLR is part of immune system, which will respond to PAMP.…”