PTEN and PI-3 kinase inhibitors control LPS signaling and the lymphoproliferative response in the CD19+ B cell compartment

Exp Cell Res. 2014 Sep 10;327(1):78-90. doi: 10.1016/j.yexcr.2014.05.016. Epub 2014 May 29.


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.

Keywords: AKT; B cells; CD19; Lymphoid; NF-κB; PI-3 kinase; PTEN; TLR.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antigens, CD / metabolism
  • Antigens, CD19 / metabolism*
  • B-Lymphocytes / drug effects
  • B-Lymphocytes / metabolism*
  • Cell Proliferation / drug effects*
  • Chromones / pharmacology
  • Cyclin D1 / metabolism
  • Interleukins / metabolism
  • Lipopolysaccharides / pharmacology*
  • Lymphocyte Activation / drug effects
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • NF-kappa B / metabolism
  • Oligopeptides / pharmacology
  • PTEN Phosphohydrolase / antagonists & inhibitors*
  • Phosphoinositide-3 Kinase Inhibitors*
  • Proto-Oncogene Proteins c-myb / metabolism
  • Signal Transduction / drug effects*
  • Toll-Like Receptor 4 / metabolism
  • Vesicular Transport Proteins


  • Antigens, CD
  • Antigens, CD19
  • Ccnd1 protein, mouse
  • Chromones
  • Interleukins
  • Lipopolysaccharides
  • Ly78 protein, mouse
  • NF-kappa B
  • Oligopeptides
  • Phosphoinositide-3 Kinase Inhibitors
  • Proto-Oncogene Proteins c-myb
  • SF 1126
  • TXLNA protein, mouse
  • Toll-Like Receptor 4
  • Vesicular Transport Proteins
  • Cyclin D1
  • PTEN Phosphohydrolase
  • Pten protein, mouse