Abstract
Class IA phosphoinositide 3-kinases (PI3Ks) are essential to function of normal and tumor cells, and to modulate immune responses. T lymphocytes express high levels of p110α and p110δ class IA PI3K. Whereas the functioning of PI3K p110δ in immune and autoimmune reactions is well established, the role of p110α is less well understood. Here, a novel dual p110α/δ inhibitor (ETP-46321) and highly specific p110α (A66) or p110δ (IC87114) inhibitors have been compared concerning T cell activation in vitro, as well as the effect on responses to protein antigen and collagen-induced arthritis in vivo. In vitro activation of naive CD4(+) T lymphocytes by anti-CD3 and anti-CD28 was inhibited more effectively by the p110δ inhibitor than by the p110α inhibitor as measured by cytokine secretion (IL-2, IL-10, and IFN-γ), T-bet expression and NFAT activation. In activated CD4(+) T cells re-stimulated through CD3 and ICOS, IC87114 inhibited Akt and Erk activation, and the secretion of IL-2, IL-4, IL-17A, and IFN-γ better than A66. The p110α/δ inhibitor ETP-46321, or p110α plus p110δ inhibitors also inhibited IL-21 secretion by differentiated CD4(+) T follicular (Tfh) or IL-17-producing (Th17) helper cells. In vivo, therapeutic administration of ETP-46321 significantly inhibited responses to protein antigen as well as collagen-induced arthritis, as measured by antigen-specific antibody responses, secretion of IL-10, IL-17A or IFN-γ, or clinical symptoms. Hence, p110α as well as p110δ Class IA PI3Ks are important to immune regulation; inhibition of both subunits may be an effective therapeutic approach in inflammatory autoimmune diseases like rheumatoid arthritis.
Keywords:
A-66; CD28; ETP-46321; IC-87114; ICOS; PI3K inhibitors; Phosphatidyl inositol-3 kinase; Rheumatoid arthritis; T lymphocytes.
Copyright © 2016 Elsevier Inc. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antibodies / pharmacology
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Arthritis, Experimental / drug therapy*
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Arthritis, Experimental / enzymology
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Arthritis, Experimental / immunology
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Arthritis, Experimental / pathology
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CD28 Antigens / genetics
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CD28 Antigens / immunology
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CD3 Complex / genetics
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CD3 Complex / immunology
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CD4-Positive T-Lymphocytes / drug effects*
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CD4-Positive T-Lymphocytes / enzymology
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CD4-Positive T-Lymphocytes / immunology
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CD4-Positive T-Lymphocytes / pathology
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Class Ia Phosphatidylinositol 3-Kinase / genetics
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Class Ia Phosphatidylinositol 3-Kinase / immunology
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Enzyme Inhibitors / pharmacology*
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Extracellular Signal-Regulated MAP Kinases / genetics
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Extracellular Signal-Regulated MAP Kinases / immunology
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Gene Expression
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Imidazoles / pharmacology*
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Interferon-gamma / genetics
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Interferon-gamma / immunology
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Interleukin-10 / genetics
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Interleukin-10 / immunology
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Interleukin-2 / genetics
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Interleukin-2 / immunology
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Lymph Nodes / drug effects
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Lymph Nodes / enzymology
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Lymph Nodes / immunology
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Lymph Nodes / pathology
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Lymphocyte Activation / drug effects
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Mice
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Mice, Inbred C57BL
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NFATC Transcription Factors / genetics
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NFATC Transcription Factors / immunology
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Phosphoinositide-3 Kinase Inhibitors*
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Protein Subunits / antagonists & inhibitors*
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Protein Subunits / genetics
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Protein Subunits / immunology
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Proto-Oncogene Proteins c-akt / genetics
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Proto-Oncogene Proteins c-akt / immunology
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Pyrazines / pharmacology*
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T-Box Domain Proteins / genetics
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T-Box Domain Proteins / immunology
Substances
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Antibodies
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CD28 Antigens
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CD3 Complex
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ETP-46321
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Enzyme Inhibitors
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IL10 protein, mouse
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Imidazoles
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Interleukin-2
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NFATC Transcription Factors
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Phosphoinositide-3 Kinase Inhibitors
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Protein Subunits
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Pyrazines
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T-Box Domain Proteins
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T-box transcription factor TBX21
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Interleukin-10
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Interferon-gamma
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Class Ia Phosphatidylinositol 3-Kinase
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Akt1 protein, mouse
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Akt2 protein, mouse
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Proto-Oncogene Proteins c-akt
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Extracellular Signal-Regulated MAP Kinases