title: Cutting edge: regulation of TLR4-driven B cell proliferation by RP105 is not B cell autonomous.
abstract: Mechanistic understanding of RP105 has been confounded by the fact that this TLR homolog has appeared to have opposing, cell type-specific effects on TLR4 signaling. Although RP105 inhibits TLR4-driven signaling in cell lines and myeloid cells, impaired LPS-driven proliferation by B cells from RP105(-/-) mice has suggested that RP105 facilitates TLR4 signaling in B cells. In this article, we show that modulation of B cell proliferation by RP105 is not a function of B cell-intrinsic expression of RP105, and identify a mechanistic role for dysregulated BAFF expression in the proliferative abnormalities of B cells from RP105(-/-) mice: serum BAFF levels are elevated in RP105(-/-) mice, and partial BAFF neutralization rescues aberrant B cell proliferative responses in such mice. These data indicate that RP105 does not have dichotomous effects on TLR4 signaling and emphasize the need for caution in interpreting the results of global genetic deletion.
authors.affiliation: Division of Molecular Immunology, Cincinnati Children's Hospital Research Foundation, Cincinnati, OH 45229, USA.
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Allen
authors.forename: Leah M
authors.initials: LM
authors.lastname: Flick
authors.forename: Senad
authors.initials: S
authors.lastname: Divanovic
authors.forename: Shaun W
authors.initials: SW
authors.lastname: Jackson
authors.forename: Richard
authors.initials: R
authors.lastname: Bram
authors.forename: David J
authors.initials: DJ
authors.lastname: Rawlings
authors.forename: Fred D
authors.initials: FD
authors.lastname: Finkelman
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Karp
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000502:physiology*; D053264:B-Cell Activating Factor / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000097:blood; D016175:B-Lymphocyte Subsets / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism; D049109:Cell Proliferation; D002478:Cells, Cultured; D020868:Gene Silencing / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D051197:Toll-Like Receptor 4 / Q000502:physiology*
chemical_list: D015703:Antigens, CD; D053264:B-Cell Activating Factor; C490500:Ly78 protein, mouse; C493487:Tlr4 protein, mouse; C505720:Tnfsf13b protein, mouse; D051197:Toll-Like Receptor 4