title: Requirement for MD-1 in cell surface expression of RP105/CD180 and B-cell responsiveness to lipopolysaccharide.
abstract: RP105 is a B-cell surface molecule that has been recently assigned as CD180. RP105 ligation with an antibody induces B-cell activation in humans and mice, leading to proliferation and up-regulation of a costimulatory molecule, B7.2/CD86. RP105 is associated with an extracellular molecule, MD-1. RP105/MD-1 has structural similarity to Toll-like receptor 4 (TLR4)/MD-2. TLR4 signals a membrane constituent of Gram-negative bacteria, lipopolysaccharide (LPS). MD-2 is indispensable for TLR4-dependent LPS responses because cells expressing TLR4/MD-2, but not TLR4 alone, respond to LPS. RP105 also has a role in LPS responses because B cells lacking RP105 show hyporesponsiveness to LPS. Little is known, however, regarding whether MD-1 is important for RP105-dependent LPS responses, as MD-2 is for TLR4. To address the issue, we developed mice lacking MD-1 and generated monoclonal antibodies (mAbs) to the protein. MD-1-null mice showed impairment in LPS-induced B-cell proliferation, antibody production, and B7.2/CD86 up-regulation. These phenotypes are similar to those of RP105-null mice. The similarity was attributed to the absence of cell surface RP105 on MD-1-null B cells. MD-1 is indispensable for cell surface expression of RP105. A role for MD-1 in LPS responses was further studied with anti-mouse MD-1 mAbs. In contrast to highly mitogenic anti-RP105 mAbs, the mAbs to MD-1 were not mitogenic but antagonistic on LPS-induced B-cell proliferation and on B7.2 up-regulation. Collectively, MD-1 is important for RP105 with respect to B-cell surface expression and LPS recognition and signaling.
authors.affiliation: Department of Immunology, Saga Medical School, Japan.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Nagai
authors.forename: Rintaro
authors.initials: R
authors.lastname: Shimazu
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Ogata
authors.forename: Sachiko
authors.initials: S
authors.lastname: Akashi
authors.forename: Katsuko
authors.initials: K
authors.lastname: Sudo
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Yamasaki
authors.forename: Shin-Ichi
authors.initials: S
authors.lastname: Hayashi
authors.forename: Yoichiro
authors.initials: Y
authors.lastname: Iwakura
authors.forename: Masao
authors.initials: M
authors.lastname: Kimoto
authors.forename: Kensuke
authors.initials: K
authors.lastname: Miyake
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000096:biosynthesis / Q000494:pharmacology; D015703:Antigens, CD; D000954:Antigens, Surface / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000502:physiology*; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D004347:Drug Interactions; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D013154:Spleen / Q000166:cytology
chemical_list: D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000954:Antigens, Surface; C115213:LY86 protein, human; D008070:Lipopolysaccharides; C490500:Ly78 protein, mouse