title: Proteolysis of interleukin-6 receptor (IL-6R) by Porphyromonas gingivalis cysteine proteinases (gingipains) inhibits interleukin-6-mediated cell activation.
abstract: Current consensus is that periodontitis is an infectious disease in which a deregulated chronic inflammatory reaction not only may lead to periodontal tissue damage but also eventually may cause tooth loss. In controlling the inflammatory state the interplay between a network of cytokines and their receptors plays an important role. Here we show that the interleukin-6 receptor (IL-6R) is rapidly and efficiently inactivated by gingipains, the arginine- (HRgpA and RgpB) and lysine- (Kgp) specific cysteine proteinases from Porphyromonas gingivalis. Preincubation of HepG2 cells with active gingipains results in the loss of gp80 (CD126) from the cell surface. This also correlates with a decreased responsiveness to stimulation by interleukin-6 (IL-6), as determined by measurement of the status of IL-6R-mediated STAT 3 (Signal Transducer and Activator of Transcription 3) activation by this cytokine. Significantly, incubation of cells with gingipains was not accompanied by release of the soluble receptor, indicating its degradation, and this was confirmed by susceptibility of the recombinant, soluble receptor to proteolytic digestion by these enzymes. With the exception of the degradation of soluble IL-6R (sIL-6R) by Kgp, all of these reactions were also observed in the presence of serum suggesting that receptor inactivation may occur in vivo. Interestingly, Kgp, although less effective in cleaving sIL-6R, was able to decrease cell responsiveness to IL-6, possibly through degradation/inactivation of the signal transducing component (gp130) associated with IL-6R. These data, together with previous observation that IL-6 itself is inactivated by gingipains, suggest that at periodontitis sites infected by P. gingivalis the inflammatory reactions dependent on IL-6 could be severely hindered contributing to both tissue damage and periodontopathogen survival.
authors.affiliation: Institute of Molecular Biology, Jagellonian University, Krakow, Poland
authors.forename: Aneta
authors.initials: A
authors.lastname: Oleksy
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Banbula
authors.forename: Marcin
authors.initials: M
authors.lastname: Bugno
authors.forename: James
authors.initials: J
authors.lastname: Travis
authors.forename: Jan
authors.initials: J
authors.lastname: Potempa
mesh_terms: D018829:Adhesins, Bacterial; D016866:Bacteroidaceae Infections / Q000276:immunology / Q000382:microbiology; D001798:Blood Proteins / Q000494:pharmacology; D015153:Blotting, Western; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D015536:Down-Regulation; D004797:Enzyme-Linked Immunosorbent Assay; D000080867:Gingipain Cysteine Endopeptidases; D006388:Hemagglutinins / Q000378:metabolism*; D006801:Humans; D015850:Interleukin-6 / Q000494:pharmacology*; D016966:Porphyromonas gingivalis / Q000201:enzymology*; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D019947:Receptors, Interleukin-6 / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D012995:Solubility; D014407:Tumor Cells, Cultured
chemical_list: D018829:Adhesins, Bacterial; D001798:Blood Proteins; D015853:Cysteine Proteinase Inhibitors; D000080867:Gingipain Cysteine Endopeptidases; D006388:Hemagglutinins; D015850:Interleukin-6; D019947:Receptors, Interleukin-6; C113250:interleukin-6 receptor alpha; D003546:Cysteine Endopeptidases