title: Cell activation by Porphyromonas gingivalis lipid A molecule through Toll-like receptor 4- and myeloid differentiation factor 88-dependent signaling pathway.
abstract: Porphyromonas gingivalis lipopolysaccharide (LPS) and its bioactive center, lipid A, are known to exhibit very low endotoxic activities and activate LPS-hyporesponsive C3H/HeJ mice that have a point mutation in the cytoplasmic portion of Toll-like receptor (TLR) 4, in contrast to classical enterobacterial LPS and their lipid A. In the present study, we attempted to determine which TLR mediates the response to lipid A from P. gingivalis strain 381. P. gingivalis LPS and its natural lipid A fraction induced NF-kappa B activation primarily in Ba/F3 cells expressing mouse TLR 2 (Ba/mTLR2), rather than in those expressing mouse TLR4 and its accessory protein MD2 (Ba/mTLR4/mMD2). Further purification of the natural lipid A fraction resulted in a significant decrease of NF-kappa B activation in Ba/mTLR2, although not in Ba/mTLR4/mMD2. The synthetic counterpart of P. gingivalis strain 381-lipid A (compound PG-381) also elicited NF-kappa B activation in Ba/mTLR4/mMD2, but not Ba/mTLR2. Furthermore, P. gingivalis purified natural lipid A and compound PG-381 lacked the ability to activate gingival fibroblasts from C3H/HeJ, TLR4 knockout (KO) and myeloid differentiation factor 88 (MyD88) KO mice. These findings demonstrate that the P. gingivalis lipid A molecule induces cell activation via a TLR4/MD2-MyD88-dependent pathway, and suggest the possibility that unknown bacterial components in P. gingivalis LPS and its lipid A may induce cell activation via TLR2.
authors.affiliation: Department of Oral Microbiology, Asahi University School of Dentistry, 1851 Hozumi, Hozumi-Cho, Motosu-Gun, Gifu 501-0296, Japan. tomo527@dent.asahi-u.ac.jp
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Ogawa
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Asai
authors.forename: Masahito
authors.initials: M
authors.lastname: Hashimoto
authors.forename: Osamu
authors.initials: O
authors.lastname: Takeuchi
authors.forename: Tomoko
authors.initials: T
authors.lastname: Kurita
authors.forename: Yasunobu
authors.initials: Y
authors.lastname: Yoshikai
authors.forename: Kensuke
authors.initials: K
authors.lastname: Miyake
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000943:Antigens, Differentiation / Q000235:genetics / Q000378:metabolism*; D016207:Cytokines / Q000276:immunology; D029721:Drosophila Proteins; D005347:Fibroblasts / Q000276:immunology / Q000378:metabolism; D005881:Gingiva / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D008050:Lipid A / Q000276:immunology / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B / Q000378:metabolism; D016966:Porphyromonas gingivalis / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology / Q000502:physiology*; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000943:Antigens, Differentiation; D016207:Cytokines; D029721:Drosophila Proteins; D008050:Lipid A; D008562:Membrane Glycoproteins; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors