In vivo induction of proinflammatory cytokines in mouse tissue by Porphyromonas gingivalis and Actinobacillus actinomycetemcomitans

Kesavalu, Lakshmyya; Chandrasekar, Bysani; Ebersole, Jeffrey L.

doi:10.1034/j.1399-302x.2002.170307.x

Cited by 70 publications

(60 citation statements)

References 35 publications

(35 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Our results revealed that P. gingivalis induces cytokine responses in our model, in accordance with the results reported by Sandros et al (39), who demonstrated that P. gingivalis can induce a strong cytokine response in primary cultures of pocket epithelium. The induction of cytokine expression following P. gingivalis infection was also reported for a mouse model (19).…”

Section: Discussionmentioning

confidence: 97%

In Vitro Models of Tissue Penetration and Destruction by Porphyromonas gingivalis

2004

View full text Add to dashboard Cite

Porphyromonas gingivalis is a gram-negative anaerobic bacterium that is considered the key etiologic agent of chronic periodontitis. Arg-and Lys-gingipain cysteine proteinases produced by P. gingivalis are key virulence factors and are believed to be essential for significant tissue component degradation, leading to host tissue invasion by periodontopathogens. Two in vitro models were used to determine the extent to which P. gingivalis can reach connective tissue. The tissue penetration potential of P. gingivalis was first investigated by using an engineered human oral mucosa model composed of normal human epithelial cells and fibroblasts. Internalized bacteria were assessed by transmission electron microscopy. Bacteria were observed within multilayered gingival epithelial cells and in the space between the stratified epithelium and the lamina propria. A gingipainnull mutant strain of P. gingivalis was found to be less potent in penetrating tissue than the wild-type strain. Proinflammatory responses to P. gingivalis infection were evaluated. P. gingivalis increased the secretion of interleukin-1␤, interleukin-6, interleukin-8, and tumor necrosis factor alpha. In the second part of the study, the contribution of P. gingivalis gingipains to tissue penetration was investigated by using a reconstituted basement membrane model (Matrigel). The penetration of 14 C-labeled P. gingivalis cells through Matrigel was significantly reduced when leupeptin, a specific inhibitor of Arg-gingipain activity, was added or when a gingipain-null mutant was used. The results obtained with these two relevant models support the capacities of P. gingivalis to infiltrate periodontal tissue and to modulate the proinflammatory response and suggest a critical role of gingipains in tissue destruction.

show abstract

Section: Discussionmentioning

confidence: 97%

In Vitro Models of Tissue Penetration and Destruction by Porphyromonas gingivalis

2004

View full text Add to dashboard Cite

show abstract

“…However, we cannot rule out the possibility that exposure to different cytokine concentrations further alters the PMN response to Ltx. Interestingly, Kesavalu et al (12) investigated the effects of oral pathogens on the expression of TNF-␣, IL-1␤, and IL-6 in the murine calvaria in situ and consequently showed that A. actinomycetemcomitans and P. gingivalis induced the expression of the gene for TNF-␣ at the highest level (TNF-␣ Ͼ Ͼ IL-1␤ Ͼ IL-6) in the calvaria. These observations suggest that these cytokines play an important role in pathogenesis in the periodontal bacterium-infected diseases, because it is well documented that these cytokines are potent factors in host inflammatory responses.…”

Section: Discussionmentioning

confidence: 99%

Tumor Necrosis Factor Alpha Enhances Actinobacillus actinomycetemcomitans Leukotoxin-Induced HL-60 Cell Apoptosis by Stimulating Lymphocyte Function-Associated Antigen 1 Expression†

Yamaguchi¹,

Kubo²,

Masuhiro

et al. 2004

Infect Immun

View full text Add to dashboard Cite

We demonstrated previously that Actinobacillus actinomycetemcomitans leukotoxin (Ltx) is greatly able to induce apoptotic signaling in cells that are positive for lymphocyte function-associated antigen 1 (LFA-1), a cell receptor of Ltx. We investigated in this study whether inflammatory cytokines can regulate apoptosis of human leukemic HL-60 cells induced by Ltx. Of the cytokines tested, tumor necrosis factor alpha (TNF-␣) significantly enhanced the Ltx-induced cell apoptosis. Northern and Western blotting analyses showed that TNF-␣ enhanced the expression of CD11a in the cells at both the mRNA and protein levels but did not do so for CD18 expression. TNF-␣ also enhanced the binding of Ltx to the cells. We also observed by measuring the mitochondrial transmembrane potential and the generation of superoxide anion that the cytokine enhanced Ltx-induced apoptosis in HL-60 cells. In addition, interleukin-1␤ significantly enhanced Ltx-induced cell apoptosis, although the enhancing activity was lower than that of TNF-␣. These stimulatory effects of both cytokines were also observed for human polymorphonuclear leukocytes. The ability of TNF-␣ to increase cell susceptibility to Ltx could be inhibited by preincubation of the cells with a monoclonal antibody against TNF receptor 1 but not by preincubation of the cells with a monoclonal antibody against anti-TNF receptor 2. Furthermore, the results of an assay of caspase 3 intracellular activity (PhiPhiLuxG 1 D 2 ) showed that Ltxinduced caspase 3 activation was completely neutralized by CD18 antibody treatment, although significant neutralization was also observed with anti-CD11a antibody. Taken together, the results of the present study indicate that TNF-␣ acts as a potent stimulator of Ltx-induced HL-60 cell apoptosis via TNF receptor 1-mediated upregulation of LFA-1 expression.Apoptosis plays an important role in the inflammatory response, tumorigenesis, and embryonic development (10, 21). It has been shown that several pathogenic bacteria act as promoters or inhibitors of apoptosis of monocytes/macrophages (6, 9, 22). These observations suggest that several cell components and metabolic products of these bacteria are involved in an important pathogenic mechanism promoting inflammatory responses via apoptosis of monocytes/macrophages.Actinobacillus actinomycetemcomitans is a gram-negative bacterium that has been identified in several human infectious diseases, such as endocarditis, meningitis, osteomyelitis (23), and aggressive periodontitis (33). It has been demonstrated by many studies that this organism produces a 116-kDa leukotoxin (Ltx) that destroys specific target cells via an apoptotic effect (16,29). Interestingly, we clearly identified lymphocyte function-associated antigen 1 (LFA-1) as a ␤2 integrin, a cell receptor for Ltx (17). Also, we showed that the Ltx-induced apoptotic signal was initiated through LFA-1 binding of the toxin. These observations suggest that elimination of LFA-1-positive inflammatory cells such as monocytes/macrophages and neutrophils ...

show abstract

“…Moreover, nonfimbriated mutants display a reduced ability to induce periodontal disease in mice following oral inoculation (19). In this context, P. gingivalis FimA has been shown to induce proinflammatory cytokine release in macrophages (22) as well as inflammatory bone resorption (8,13).…”

mentioning

confidence: 99%

Differential Activation of Human Gingival Epithelial Cells and Monocytes by Porphyromonas gingivalis Fimbriae

2007

View full text Add to dashboard Cite

Humans develop periodontitis in response to challenge by microbial dental plaque. Inflammation begins after perturbation of gingival epithelial cells by subgingival bacteria interacting through pattern-recognition receptors, including the Toll-like receptors (TLR). Porphyromonas gingivalis is a major periodontopathogen that interacts with epithelial cells through its cell surface fimbriae (FimA), leading to colonization and/or invasion. Previous work by our group has established membrane CD14 as an essential coreceptor for TLR2-mediated activation of transfected cell lines by P. gingivalis FimA. We have shown that gingival epithelial cells express TLR2 but not CD14 on their cell surfaces. We thus speculated that P. gingivalis FimA does not readily activate epithelial innate immune responses but rather functions to promote P. gingivalis colonization in the absence of a vigorous FimA-induced response. This hypothesis was verified by the findings that primary human gingival epithelial cells responded poorly to FimA in terms of interleukin (IL)-6, IL-8, granulocyte-macrophage colony-stimulating factor, and tumor necrosis factor alpha responses, in stark contrast to the marked response to other TLR2 agonists (Pam3Cys, FSL-1) that are not strictly dependent on CD14. On the other hand, CD14-expressing human primary monocytes responded with high levels of the same cytokines to both FimA and the control TLR2 agonists. The gingival epithelial cells failed to respond to FimA even in the presence of exogenously added soluble CD14. These data indicate that the gingival epithelial cell hyporesponsiveness to FimA is attributable to the lack of membrane-expressed but not soluble CD14. In conclusion, P. gingivalis FimA differentially activates human monocytes and epithelial cells, perhaps reflecting different tactics used by P. gingivalis when interacting with different host cell types or a host strategy to limit inflammation.Porphyromonas gingivalis is a gram-negative, black-pigmented bacterium associated with periodontal disease, a condition which results in destruction of the tooth-supporting tissues and loss of teeth (16). P. gingivalis expresses virulence factors involved in host tissue destruction and immune perturbation (10). Adhesion molecules of P. gingivalis include fimbriae (FimA) and hemagglutinins; however, P. gingivalis FimA is considered a critical determinant for the attachment of this microorganism in the oral cavity (16). In this regard, there is strong evidence supporting a crucial role for FimA in P. gingivalis adhesion to several mammalian cells types; indeed, nonfimbriated mutants of P. gingivalis, constructed by inactivation of the FimA gene, display reduced adhesion and invasion of epithelial cells compared to wild-type P. gingivalis (29). Moreover, nonfimbriated mutants display a reduced ability to induce periodontal disease in mice following oral inoculation (19). In this context, P. gingivalis FimA has been shown to induce proinflammatory cytokine release in macrophages (22) as well as inflammatory bon...

show abstract

In vivo induction of proinflammatory cytokines in mouse tissue by Porphyromonas gingivalis and Actinobacillus actinomycetemcomitans

Cited by 70 publications

References 35 publications

In Vitro Models of Tissue Penetration and Destruction by Porphyromonas gingivalis

In Vitro Models of Tissue Penetration and Destruction by Porphyromonas gingivalis

Tumor Necrosis Factor Alpha Enhances Actinobacillus actinomycetemcomitans Leukotoxin-Induced HL-60 Cell Apoptosis by Stimulating Lymphocyte Function-Associated Antigen 1 Expression†

Differential Activation of Human Gingival Epithelial Cells and Monocytes by Porphyromonas gingivalis Fimbriae

Contact Info

Product

Resources

About