Inactivation of tumor necrosis factor-alpha by proteinases (gingipains) from the periodontal pathogen, Porphyromonas gingivalis. Implications of immune evasion.
Porphyromonas gingivalis is one of the major pathogens associated with adult periodontitis, a major chronic inflammatory disease. Potent proteinases elaborated by these bacteria aid directly and indirectly in both the development of the pathophysiology of the disease and in host defense evasion. For these reasons they are considered key virulence factors. To investigate whether possible immune evasion mechanisms involve the dysregulation of the host cytokine network, we examined the ability of P. gingivalis cysteine proteinases, including Arg-specific gingipains HRGP and RGP2 and Lys-specific KGP, to degrade the proinflammatory cytokine tumor necrosis factor-alpha (TNF-alpha). All three gingipains rapidly degraded TNF-alpha as exhibited by immunoblot analysis. Moreover, all biological activity was significantly reduced over extended incubation periods with the proteinases tested, whereas the host neutrophil proteinases were ineffective. These results indicate that the gingipain proteinases elaborated by P. gingivalis are capable of disrupting the cytokine network at the site of infection through the degradation of the proinflammatory cytokine TNF-alpha, suggesting the removal of one of several mediators important to the function of polymorphonuclear leukocytes. Such a mechanism is likely to be utilized by other infective organisms not only for survival but also for growth and proliferation.
Calkins
C C
CC
Department of Biochemistry and Molecular Biology, University of Georgia, Athens, Georgia 30602, USA.
Platt
K
K
Potempa
J
J
Travis
J
J
D018829:Adhesins, Bacterial; D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D000080867:Gingipain Cysteine Endopeptidases; D006388:Hemagglutinins / Q000378:metabolism*; D006868:Hydrolysis; D051379:Mice; D008969:Molecular Sequence Data; D016966:Porphyromonas gingivalis / Q000201:enzymology* / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*
D018829:Adhesins, Bacterial; D000080867:Gingipain Cysteine Endopeptidases; D006388:Hemagglutinins; D014409:Tumor Necrosis Factor-alpha; D003546:Cysteine Endopeptidases