Porphyromonas gingivalisGingipain-R Enhances Interleukin-8 but Decreases Gamma Interferon-Inducible Protein 10 Production by Human Gingival Fibroblasts in Response to T-Cell Contact

Abstract

Proteases produced by Porphyromonas gingivalis, an oral pathogen, are considered important virulence factors and may affect the responses of cells equipped with proteinase-activated receptors. The aim of this study was to investigate the effect of the arginine-specific cysteine protease gingipain-R produced by P. gingivalis on chemokine production by human gingival fibroblasts (HGF) and the effect of gingipain-R treatment on the subsequent contact-dependent activation of HGF by T cells. HGF incubated in the presence of purified 47-kDa gingipain-R showed increased levels of interleukin-8 (IL-8) mRNA. Cyclooxygenase-2 (COX-2) mRNA was also induced. Further exposure of HGF to activated T cells resulted in the dose-and time-dependent enhancement of IL-8 transcription and release. T-cell membrane-bound tumor necrosis factor (TNF) was the ligand inducing IL-8 production by HGF, since TNF neutralization abrogated HGF responses to T-cell contact. The enhanced IL-8 release was due, at least in part, to prostaglandin-E 2 production, which was mostly blocked by indomethacin. Gingipain-R proteolytic activity was required since heat inactivation, specific synthetic protease inhibitors, and the natural substrate competitor histatin 5 abrogated its effects. The enhanced production of IL-8 in response to T-cell contact was specific since monocyte chemotactic protein-1 (MCP-1) production was unaffected while interferon-gamma-inducible protein-10 (IP-10) was inhibited. The sum of these activities may result in the recruitment of differential cell types to sites of inflammation since IL-8 preferentially recruits neutrophils and IP-10 attracts activated T cells and may be relevant to the pathogenesis of periodontitis.

Suppression of T-Cell Chemokines by Porphyromonas gingivalis

“…Mutants lacking the major or minor fimbriae of P. gingivalis did not show a loss of IP-10 inhibition (our unpublished data). Other studies have reported that the arginine-specific gingipain of P. gingivalis can suppress IP-10 in gingival fibroblasts stimulated with T cells (50). As IP-10 mRNA levels were reduced by the protease, the role of the enzyme extends beyond proteolytic degradation of IP-10.…”

Small bowel cyclooxygenase 2 (COX-2) expression in patients with IgA nephropathy

“…During both acute and chronic intestinal inflammation, myofibroblasts have been observed to be sites of COX-2-derived prostaglandin synthesis [24,28]. One factor triggering this type of response is infection [29,30].…”

The RgpA-Kgp Proteinase-Adhesin Complexes ofPorphyromonas gingivalisInactivate the Th2 Cytokines Interleukin-4 and Interleukin-5

“…Stimulation of human epithelial cells and fibroblasts with P. gingivalis cells in vitro resulted in an upregulation of the proinflammatory cytokines IL-1␤, IL-6, IL-8, and TNF-␣ (1). In a similar study, a proinflammatory cytokine, IL-8, was also demonstrated to be upregulated after stimulation of human gingival fibroblasts with the P. gingivalis Arg-specific proteinase in vitro (24). IL-17, another proinflammatory cytokine, has been found in periodontal lesions, indicating it may play a role in Th1 modulation (38).…”