Related Experiment Videos

PI3 kinase δ is a key regulator of synoviocyte function in rheumatoid arthritis

Beatrix Bartok1, David L Boyle, Yi Liu

  • 1Division of Rheumatology, Allergy, and Immunology, University of California San Diego School of Medicine, La Jolla, California 92093, USA.

The American Journal of Pathology
|March 22, 2012
PubMed

Insights

Class I phosphoinositide 3 kinase delta (PI3Kδ) is elevated in rheumatoid arthritis (RA) synovium and fibroblast-like synoviocytes. Targeting PI3Kδ may offer new RA therapies by modulating fibroblast function.

Area of Science:

  • Immunology
  • Molecular Biology
  • Rheumatology

Background:

  • Class I phosphoinositide 3 kinase delta (PI3Kδ) is a key regulator of leukocyte function and a potential therapeutic target for rheumatoid arthritis (RA).
  • The role of PI3Kδ in fibroblast-like synoviocytes (FLS) within the RA synovium remains uncharacterized, representing a gap in understanding RA pathogenesis and PI3Kδ's therapeutic potential.

Purpose of the Study:

  • To investigate the expression and functional significance of PI3Kδ in the RA synovium and cultured FLS.
  • To determine if PI3Kδ plays a role in fibroblast proliferation and survival.

Main Methods:

  • Immunohistochemistry was used to assess PI3Kδ expression in RA and osteoarthritis (OA) synovium.
  • Quantitative PCR and Western blot analysis were employed to measure PI3Kδ mRNA and protein levels in synovial tissues and cultured FLS.
  • Pharmacological inhibitors, including a selective PI3Kδ inhibitor (INK007), were used to probe the function of PI3Kδ in FLS stimulated with cytokines and growth factors.

Main Results:

  • PI3Kδ was highly expressed in RA synovium, particularly in the synovial lining, and showed increased mRNA and protein levels compared to OA synovium.
  • Cultured FLS expressed PI3Kδ, PI3Kα, and PI3Kβ, with PI3Kδ expression selectively upregulated by tumor necrosis factor (TNF) and interleukin-1 (IL-1).
  • PI3Kδ inhibition blocked PDGF- and TNF-induced Akt activation, reduced PDGF-mediated FLS proliferation, and increased apoptosis induced by hydrogen peroxide (H₂O₂).

Conclusions:

  • This study provides the first evidence of increased PI3Kδ expression in both RA synovium and cultured synoviocytes.
  • PI3Kδ is a critical regulator of PDGF-mediated fibroblast growth and survival through the Akt pathway.
  • Targeting PI3Kδ presents a potential anti-inflammatory and disease-modifying therapeutic strategy for RA by impacting synoviocyte function.

Related Concept Videos

The JAK-STAT Signaling Pathway01:20

The JAK-STAT Signaling Pathway

Several cytokine receptors have tightly bound Janus kinase or JAK proteins attached at their cytosolic tail. Small signaling molecules such as cytokines, growth hormones, or prolactins bind to the cytokine receptors and initiate their dimerization. The dimerization brings the cytosolic JAKs together that trans-phosphorylate and activates each other. The activated JAKs now phosphorylate cytosolic tails of the cytokine receptors, which serve as binding sites for adaptor proteins such as  SH2...
PI3K/mTOR/AKT Signaling Pathway01:22

PI3K/mTOR/AKT Signaling Pathway

The mammalian target of rapamycin  (mTOR) is a serine/threonine kinase that regulates growth, proliferation, and cell survival in response to hormones, growth factors, or nutrient availability. This kinase exists in two structurally and functionally distinct forms: mTOR complex 1  (mTORC1) and mTOR complex 2  (mTORC2). The first form (mTORC1) is composed of a rapamycin-sensitive Raptor and proline-rich Akt substrate, PRAS40. In contrast,  mTORC2 consists of a rapamycin-insensitive companion...
T Cell Types and Functions01:24

T Cell Types and Functions

When T cells with CD4 markers are activated, they give rise to two types of effector cells: helper T cells and regulatory T cells. Meanwhile, T cells with CD8 markers differentiate into effector cytotoxic T cells. The differentiation of CD4 T cells into helper T cell subsets, such as Th1, Th2, and Th17 cells, is dependent on the antigen type, antigen-presenting cell, and regulatory cytokines.
Th1 cells stimulate dendritic cells to express necessary co-stimulatory molecules on their surfaces for...
IP3/DAG Signaling Pathway01:11

IP3/DAG Signaling Pathway

Membrane lipids such as phosphatidylinositol (PI) are precursors for several membrane-bound and soluble second messengers. Specific kinases phosphorylate PI and produce phosphorylated inositol phospholipids. One such inositol phospholipids are the  phosphatidylinositol-4,5 bisphosphate [PI(4,5)P2], present in the inner half of the lipid bilayer. Upon ligand binding, GPCR stimulates Gq proteins to turn on phospholipase Cꞵ. Activated phospholipase Cꞵ cleaves PI(4,5)P2 and produces two-second...
NF-κB-dependent Signaling Pathway02:26

NF-κB-dependent Signaling Pathway

The transcription factor NF-κB was discovered in 1986 in the lab of Nobel laureate Professor David Baltimore, for its interaction with the immunoglobulin light chain enhancer in B-cells. After more than three decades of study, it is now evident that NF-κB regulates the expression of over 100 genes. Most of these genes play an essential role in the innate and adaptive immune responses as well as the inflammatory responses of animals.
NF-κB-dependent Signaling Mechanism
The heterodimer of NF-κB...
NF-kB-dependent Signaling Pathway02:26

NF-kB-dependent Signaling Pathway

The transcription factor NF-κB was discovered in 1986 in the lab of Nobel laureate Professor David Baltimore, for its interaction with the immunoglobulin light chain enhancer in B-cells. After more than three decades of study, it is now evident that NF-κB regulates the expression of over 100 genes. Most of these genes play an essential role in the innate and adaptive immune responses as well as the inflammatory responses of animals.
NF-κB-dependent Signaling Mechanism
The heterodimer of NF-κB...