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Infection and Immunity, March 2005, p. 1506-1514, Vol. 73, No. 3
0019-9567/05/$08.00+0 doi:10.1128/IAI.73.3.1506-1514.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.
Inactivation of Membrane Tumor Necrosis Factor Alpha by Gingipains from Porphyromonas gingivalis
Renata M
yk-Kope
,1
Ma
gorzata Bzowska,2
Jan Potempa,3
Monika Bzowska,1
Natalia Jura,1,
Aneta Sroka,3
Roy A. Black,4 and
Joanna Bereta1*
Department of Cell Biochemistry,1 Department of Immunology,2 Department of Microbiology, Faculty of Biotechnology, Jagiellonian University, Cracow, Poland,3 Amgen Inc., Seattle, Washington4
Received 3 September 2004/ Returned for modification 6 October 2004/ Accepted 26 October 2004
Gingipains are cysteine proteinases produced by Porphyromonas gingivalis, a major causative bacterium of adult periodontitis. They consist of arginine-specific (HRgpA and RgpB) and lysine-specific (Kgp) proteinases. Gingipains strongly affect the host defense system by degrading some cytokines, components of the complement system, and several immune cell receptors. In an in vitro model, gingipains were shown to degrade soluble tumor necrosis factor alpha (TNF-
). However, since membrane TNF- shows strong biological activity, especially in local inflammatory lesions, it was worth investigating whether gingipains might also destroy membrane TNF- and limit its biological activities. To avoid a possible influence of gingipains on ADAM17, the secretase of TNF-, the majority of experiments were performed using ADAM17–/– fibroblasts stably transfected with cDNA of human pro-TNF- (ADAM17–/– TNF+). Arginine-specific gingipains (Rgp's) strongly diminished the level of TNF- on the cell surface as measured by flow cytometry, and this process was not accompanied by an increased concentration of soluble TNF- in the culture medium. Degradation of membrane TNF- by Rgp's correlated with a strong decrease in TNF--mediated biological activities of ADAM17–/– TNF+ cells. First, the activation state of transcription factor NF-
B was suppressed; second, the cells were no longer able to induce apoptosis in HL-60 cells. Kgp was also able to cleave membrane TNF-, but its effect was much weaker than that of Rgp's. Gingipains also limited the binding of native TNF- to the target cells. Thus, gingipains are able not only to cleave soluble TNF- but also to destroy the membrane form of the cytokine, which may additionally dysregulate the cytokine network.
* Corresponding author. Mailing address: Faculty of Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387 Cracow, Poland. Phone: 48-12-664 6356. Fax: 48-12-664 6902. E-mail: joannab{at}mol.uj.edu.pl.
Present address: Department of Molecular Genetics and Microbiology, State University of New York at Stony Brook, Stony Brook, N.Y.
Infection and Immunity, March 2005, p. 1506-1514, Vol. 73, No. 3
0019-9567/05/$08.00+0 doi:10.1128/IAI.73.3.1506-1514.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.
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