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{sup 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 exaggeratedmore »
- Authors:
-
- UCSD Department of Pediatrics, Moores UCSD Cancer Center, University of California School of Medicine, San Diego, CA 92093 (United States)
- Department of Pediatrics, Emory University School of Medicine, Atlanta, GA (United States)
- Publication Date:
- OSTI Identifier:
- 22416927
- Resource Type:
- Journal Article
- Journal Name:
- Experimental Cell Research
- Additional Journal Information:
- Journal Volume: 327; Journal Issue: 1; Other Information: Copyright (c) 2014 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); Journal ID: ISSN 0014-4827
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 60 APPLIED LIFE SCIENCES; CELL PROLIFERATION; COMPARTMENTS; GROWTH FACTORS; IN VIVO; LYMPHOCYTES; MORPHOLOGY; NEOPLASMS; PATHOGENESIS; PATTERN RECOGNITION; PHENOTYPE; RECEPTORS; SIGNALS; SPLEEN; SPLENOMEGALY; TRANSGENIC MICE
Citation Formats
Singh, Alok R., Peirce, Susan K., Joshi, Shweta, Durden, Donald L., E-mail: ddurden@ucsd.edu, and Division of Pediatric Hematology-Oncology, UCSD Rady Children's Hospital, La Jolla, CA. PTEN and PI-3 kinase inhibitors control LPS signaling and the lymphoproliferative response in the CD19+ B cell compartment. United States: N. p., 2014.
Web. doi:10.1016/J.YEXCR.2014.05.016.
Singh, Alok R., Peirce, Susan K., Joshi, Shweta, Durden, Donald L., E-mail: ddurden@ucsd.edu, & Division of Pediatric Hematology-Oncology, UCSD Rady Children's Hospital, La Jolla, CA. PTEN and PI-3 kinase inhibitors control LPS signaling and the lymphoproliferative response in the CD19+ B cell compartment. United States. https://doi.org/10.1016/J.YEXCR.2014.05.016
Singh, Alok R., Peirce, Susan K., Joshi, Shweta, Durden, Donald L., E-mail: ddurden@ucsd.edu, and Division of Pediatric Hematology-Oncology, UCSD Rady Children's Hospital, La Jolla, CA. 2014.
"PTEN and PI-3 kinase inhibitors control LPS signaling and the lymphoproliferative response in the CD19+ B cell compartment". United States. https://doi.org/10.1016/J.YEXCR.2014.05.016.
@article{osti_22416927,
title = {PTEN and PI-3 kinase inhibitors control LPS signaling and the lymphoproliferative response in the CD19+ B cell compartment},
author = {Singh, Alok R. and Peirce, Susan K. and Joshi, Shweta and Durden, Donald L., E-mail: ddurden@ucsd.edu and Division of Pediatric Hematology-Oncology, UCSD Rady Children's Hospital, La Jolla, CA},
abstractNote = {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{sup 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. - Highlights: • First genetic evidence that PTEN controls LPS/TLR4 signaling in B lymphocytes. • Evidence that PTEN regulates LPS induced lymphoproliferation in vivo. • PI-3 kinase inhibitors block LPS induced lymphoproliferation in vivo.},
doi = {10.1016/J.YEXCR.2014.05.016},
url = {https://www.osti.gov/biblio/22416927},
journal = {Experimental Cell Research},
issn = {0014-4827},
number = 1,
volume = 327,
place = {United States},
year = {Wed Sep 10 00:00:00 EDT 2014},
month = {Wed Sep 10 00:00:00 EDT 2014}
}