title: Pathway-selective suppression of chemokine receptor signaling in B cells by LPS through downregulation of PLC-β2.
abstract: Lymphocyte activation leads to changes in chemokine receptor expression. There are limited data, however, on how lymphocyte activators can alter chemokine signaling by affecting downstream pathways. We hypothesized that B cell-activating agents might alter chemokine responses by affecting downstream signal transducers, and that such effects might differ depending on the activator. We found that activating mouse B cells using either anti-IgM or lipopolysaccharide (LPS) increased the surface expression of CCR6 and CCR7 with large increases in chemotaxis to their cognate ligands. By contrast, while anti-IgM also led to enhanced calcium responses, LPS-treated cells showed only small changes in calcium signaling as compared with cells that were freshly isolated. Of particular interest, we found that LPS caused a reduction in the level of B-cell phospholipase C (PLC)-β2 mRNA and protein. Data obtained using PLC-β2(-/-) mice showed that the β2 isoform mediates close to one-half the chemokine-induced calcium signal in resting and anti-IgM-activated B cells, and we found that calcium signals in the LPS-treated cells were boosted by increasing the level of PLC-β2 using transfection, consistent with a functional effect of downregulating PLC-β2. Together, our results show activator-specific effects on responses through B-cell chemokine receptors that are mediated by quantitative changes in a downstream signal-transducing protein, revealing an activity for LPS as a downregulator of PLC-β2, and a novel mechanism for controlling chemokine-induced signals in lymphocytes.
authors.affiliation: Inflammation Biology Section, Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Aiko-Konno
authors.initials: AK
authors.lastname: Shirakawa
authors.forename: Fang
authors.initials: F
authors.lastname: Liao
authors.forename: Hongwei H
authors.initials: HH
authors.lastname: Zhang
authors.forename: Michael N
authors.initials: MN
authors.lastname: Hedrick
authors.forename: Satya P
authors.initials: SP
authors.lastname: Singh
authors.forename: Dianqing
authors.initials: D
authors.lastname: Wu
authors.forename: Joshua M
authors.initials: JM
authors.lastname: Farber
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology* / Q000276:immunology; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects; D018925:Chemokines / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D007075:Immunoglobulin M / Q000276:immunology; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D018448:Models, Immunological; D054799:Phospholipase C beta / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D019707:Receptors, Chemokine / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects* / Q000276:immunology; D010738:Type C Phospholipases / Q000378:metabolism
chemical_list: D018925:Chemokines; D007075:Immunoglobulin M; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D019707:Receptors, Chemokine; D017868:Cyclic AMP-Dependent Protein Kinases; D010738:Type C Phospholipases; D054799:Phospholipase C beta; D002118:Calcium