title: PTEN and PI-3 kinase inhibitors control LPS signaling and the lymphoproliferative response in the CD19+ B cell compartment.
abstract: Pattern recognition receptors (PRRs), e.g. toll receptors (TLRs) that bind ligands within the microbiome have been implicated in the pathogenesis of cancer. LPS is a ligand for two TLR family members, TLR4 and RP105 which mediate LPS signaling in B cell proliferation and migration. Although LPS/TLR/RP105 signaling is well-studied; our understanding of the underlying molecular mechanisms controlling these PRR signaling pathways remains incomplete. Previous studies have demonstrated a role for PTEN/PI-3K signaling in B cell selection and survival, however a role for PTEN/PI-3K in TLR4/RP105/LPS signaling in the B cell compartment has not been reported. Herein, we crossed a CD19cre and PTEN(fl/fl) mouse to generate a conditional PTEN knockout mouse in the CD19+ B cell compartment. These mice were further crossed with an IL-14α transgenic mouse to study the combined effect of PTEN deletion, PI-3K inhibition and expression of IL-14α (a cytokine originally identified as a B cell growth factor) in CD19+ B cell lymphoproliferation and response to LPS stimulation. Targeted deletion of PTEN and directed expression of IL-14α in the CD19+ B cell compartment (IL-14+PTEN-/-) lead to marked splenomegaly and altered spleen morphology at baseline due to expansion of marginal zone B cells, a phenotype that was exaggerated by treatment with the B cell mitogen and TLR4/RP105 ligand, LPS. Moreover, LPS stimulation of CD19+ cells isolated from these mice display increased proliferation, augmented AKT and NFκB activation as well as increased expression of c-myc and cyclinD1. Interestingly, treatment of LPS treated IL-14+PTEN-/- mice with a pan PI-3K inhibitor, SF1126, reduced splenomegaly, cell proliferation, c-myc and cyclin D1 expression in the CD19+ B cell compartment and normalized the splenic histopathologic architecture. These findings provide the direct evidence that PTEN and PI-3K inhibitors control TLR4/RP105/LPS signaling in the CD19+ B cell compartment and that pan PI-3 kinase inhibitors reverse the lymphoproliferative phenotype in vivo.
authors.affiliation: UCSD Department of Pediatrics, Moores UCSD Cancer Center, University of California School of Medicine, San Diego, CA 92093, USA.
authors.forename: Alok R
authors.initials: AR
authors.lastname: Singh
authors.affiliation: Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: Susan K
authors.initials: SK
authors.lastname: Peirce
authors.affiliation: UCSD Department of Pediatrics, Moores UCSD Cancer Center, University of California School of Medicine, San Diego, CA 92093, USA.
authors.forename: Shweta
authors.initials: S
authors.lastname: Joshi
authors.affiliation: UCSD Department of Pediatrics, Moores UCSD Cancer Center, University of California School of Medicine, San Diego, CA 92093, USA; Division of Pediatric Hematology-Oncology, UCSD Rady Children׳s Hospital, La Jolla, CA, USA. Electronic address: ddurden@ucsd.edu.
authors.forename: Donald L
authors.initials: DL
authors.lastname: Durden
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D018941:Antigens, CD19 / Q000378:metabolism*; D001402:B-Lymphocytes / Q000187:drug effects / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects*; D002867:Chromones / Q000494:pharmacology; D019938:Cyclin D1 / Q000378:metabolism; D007378:Interleukins / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000378:metabolism; D009842:Oligopeptides / Q000494:pharmacology; D051059:PTEN Phosphohydrolase / Q000037:antagonists & inhibitors*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D020598:Proto-Oncogene Proteins c-myb / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D033921:Vesicular Transport Proteins
chemical_list: D015703:Antigens, CD; D018941:Antigens, CD19; C530105:Ccnd1 protein, mouse; D002867:Chromones; D007378:Interleukins; D008070:Lipopolysaccharides; C490500:Ly78 protein, mouse; D016328:NF-kappa B; D009842:Oligopeptides; D000081082:Phosphoinositide-3 Kinase Inhibitors; D020598:Proto-Oncogene Proteins c-myb; C526549:SF 1126; C545985:TXLNA protein, mouse; D051197:Toll-Like Receptor 4; D033921:Vesicular Transport Proteins; D019938:Cyclin D1; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse
keywords: AKT; B cells; CD19; Lymphoid; NF-κB; PI-3 kinase; PTEN; TLR