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Departments of
*
Microbiology and Immunology and
Endodontics and Periodontics, Tohoku University School of Dentistry, Sendai, Japan;
Department of Immunology, Saga Medical School, Saga, Japan; and
§
Division of Molecular Pathology, Department of Neuroscience and Immunology, Kumamoto University Graduate School of Medical Science, Kumamoto, Japan
Cysteine proteinases (gingipains) elaborated from
Porphyromonas gingivalis exhibit enzymatic activities
against a broad range of host proteins and are considered key virulence
factors in the onset and development of adult periodontitis and host
defense evasion. In this study, we examined the ability of
arginine-specific gingipains (high molecular mass Arg-specific
gingipain (HRGP) and Arg-specific gingipain 2) and lysine-specific
gingipain (KGP) to cleave monocyte CD14, the main receptor for
bacterial cell surface components such as LPS. Binding of anti-CD14
mAb MY4 to human monocytes was almost completely abolished by 0.3 µM
HRGP and KGP treatments for 15 min, and 1 µM RGP2 for 30 min. In
contrast, the expressions of Toll-like receptor 4, and CD18, CD54,
CD59, and HLA-A, -B, -C on monocytes were slightly increased and
decreased, respectively, by 0.3 µM HRGP and KGP. This down-regulation
resulted from direct proteolysis, because 1) gingipains eliminated MY4
binding even to fixed monocytes, and 2) CD14 fragments were detected in
the extracellular medium by immunoblot analysis. Human rCD14 was
degraded by all three gingipains, which confirmed that CD14 was a
substrate for gingipains. TNF-
production by monocytes after HRGP
and KGP treatments was decreased at 1 ng/ml, but not at 20 µg/ml LPS,
indicating that gingipains inhibited a CD14-dependent cell activation.
These results suggest that gingipains preferentially cleave monocyte
CD14, resulting in attenuation of the cellular recognition of bacteria,
and as a consequence sustain chronic inflammation.
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