ISA-2011B, a phosphatidylinositol 4-phosphate 5-kinase a inhibitor, impairs CD28-dependent costimulatory and pro-inflammatory signals in human T lymphocytes
(2017) In Frontiers in Immunology 8(APR).- Abstract
Phosphatidylinositol 4,5-biphosphate (PIP2) is a membrane phospholipid that controls the activity of several proteins regulating cytoskeleton reorganization, cytokine gene expression, T cell survival, proliferation, and differentiation. Phosphatidylinositol 4-phosphate 5-kinases (PIP5Ks) are the main enzymes involved in PIP2 biosynthesis by phosphorylating phosphatidylinositol 4-monophosphate (PI4P) at the D5 position of the inositol ring. In human T lymphocytes, we recently found that CD28 costimulatory molecule is pivotal for PIP2 turnover by recruiting and activating PIP5Ka. We also found that PIP5Ka is the main regulator of both CD28 costimulatory signals integrating those delivered by TCR as well as CD28 autonomous signals... (More)
Phosphatidylinositol 4,5-biphosphate (PIP2) is a membrane phospholipid that controls the activity of several proteins regulating cytoskeleton reorganization, cytokine gene expression, T cell survival, proliferation, and differentiation. Phosphatidylinositol 4-phosphate 5-kinases (PIP5Ks) are the main enzymes involved in PIP2 biosynthesis by phosphorylating phosphatidylinositol 4-monophosphate (PI4P) at the D5 position of the inositol ring. In human T lymphocytes, we recently found that CD28 costimulatory molecule is pivotal for PIP2 turnover by recruiting and activating PIP5Ka. We also found that PIP5Ka is the main regulator of both CD28 costimulatory signals integrating those delivered by TCR as well as CD28 autonomous signals regulating the expression of pro-inflammatory genes. Given emerging studies linking alterations of PIP2 metabolism to immune-based diseases, PIP5Ka may represent a promising target to modulate immunity and inflammation. Herewith, we characterized a recently discovered inhibitor of PIP5Ka, ISA-2011B, for its inhibitory effects on T lymphocyte functions. We found that the inhibition of PIP5Ka lipid-kinase activity by ISA-2011B significantly impaired CD28 costimulatory signals necessary for TCR-mediated Ca2+ influx, NF-AT transcriptional activity, and IL-2 gene expression as well as CD28 autonomous signals regulating the activation of NF-κB and the transcription of pro-inflammatory cytokine and chemokine genes. Moreover, our data on the inhibitory effects of ISA-2011B on CD28-mediated upregulation of inflammatory cytokines related to Th17 cell phenotype in type 1 diabetes patients suggest ISA-2011B as a promising anti-inflammatory drug.
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- author
- Kunkl, Martina ; Porciello, Nicla ; Mastrogiovanni, Marta ; Capuano, Cristina ; Lucantoni, Federica ; Moretti, Chiara ; Persson, Jenny L. LU ; Galandrini, Ricciarda ; Buzzetti, Raffaella and Tuosto, Loretta
- organization
- publishing date
- 2017-04-26
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- CD28 co-stimulation, PIP5K, Pro-inflammatory cytokines, T lymphocytes, T1D
- in
- Frontiers in Immunology
- volume
- 8
- issue
- APR
- article number
- 502
- publisher
- Frontiers Media S. A.
- external identifiers
-
- pmid:28491063
- wos:000400313800001
- scopus:85018445653
- ISSN
- 1664-3224
- DOI
- 10.3389/fimmu.2017.00502
- language
- English
- LU publication?
- yes
- id
- 1d6bef40-5ee0-498f-a28f-64fb4cfe696b
- date added to LUP
- 2017-05-24 16:31:29
- date last changed
- 2024-03-31 10:28:05
@article{1d6bef40-5ee0-498f-a28f-64fb4cfe696b,
abstract = {{<p>Phosphatidylinositol 4,5-biphosphate (PIP2) is a membrane phospholipid that controls the activity of several proteins regulating cytoskeleton reorganization, cytokine gene expression, T cell survival, proliferation, and differentiation. Phosphatidylinositol 4-phosphate 5-kinases (PIP5Ks) are the main enzymes involved in PIP2 biosynthesis by phosphorylating phosphatidylinositol 4-monophosphate (PI4P) at the D5 position of the inositol ring. In human T lymphocytes, we recently found that CD28 costimulatory molecule is pivotal for PIP2 turnover by recruiting and activating PIP5Ka. We also found that PIP5Ka is the main regulator of both CD28 costimulatory signals integrating those delivered by TCR as well as CD28 autonomous signals regulating the expression of pro-inflammatory genes. Given emerging studies linking alterations of PIP2 metabolism to immune-based diseases, PIP5Ka may represent a promising target to modulate immunity and inflammation. Herewith, we characterized a recently discovered inhibitor of PIP5Ka, ISA-2011B, for its inhibitory effects on T lymphocyte functions. We found that the inhibition of PIP5Ka lipid-kinase activity by ISA-2011B significantly impaired CD28 costimulatory signals necessary for TCR-mediated Ca2+ influx, NF-AT transcriptional activity, and IL-2 gene expression as well as CD28 autonomous signals regulating the activation of NF-κB and the transcription of pro-inflammatory cytokine and chemokine genes. Moreover, our data on the inhibitory effects of ISA-2011B on CD28-mediated upregulation of inflammatory cytokines related to Th17 cell phenotype in type 1 diabetes patients suggest ISA-2011B as a promising anti-inflammatory drug.</p>}},
author = {{Kunkl, Martina and Porciello, Nicla and Mastrogiovanni, Marta and Capuano, Cristina and Lucantoni, Federica and Moretti, Chiara and Persson, Jenny L. and Galandrini, Ricciarda and Buzzetti, Raffaella and Tuosto, Loretta}},
issn = {{1664-3224}},
keywords = {{CD28 co-stimulation; PIP5K; Pro-inflammatory cytokines; T lymphocytes; T1D}},
language = {{eng}},
month = {{04}},
number = {{APR}},
publisher = {{Frontiers Media S. A.}},
series = {{Frontiers in Immunology}},
title = {{ISA-2011B, a phosphatidylinositol 4-phosphate 5-kinase a inhibitor, impairs CD28-dependent costimulatory and pro-inflammatory signals in human T lymphocytes}},
url = {{http://dx.doi.org/10.3389/fimmu.2017.00502}},
doi = {{10.3389/fimmu.2017.00502}},
volume = {{8}},
year = {{2017}},
}