ETP-46321, a dual p110α/δ class IA phosphoinositide 3-kinase inhibitor modulates T lymphocyte activation and collagen-induced arthritis

L Aragoneses-Fenoll; M Montes-Casado; G Ojeda; Y Y Acosta; J Herranz; S Martínez; C Blanco-Aparicio; G Criado; J Pastor; U Dianzani; P Portolés; J M Rojo

doi:10.1016/j.bcp.2016.02.005

ETP-46321, a dual p110α/δ class IA phosphoinositide 3-kinase inhibitor modulates T lymphocyte activation and collagen-induced arthritis

Biochem Pharmacol. 2016 Apr 15:106:56-69. doi: 10.1016/j.bcp.2016.02.005. Epub 2016 Feb 13.

Authors

L Aragoneses-Fenoll¹, M Montes-Casado¹, G Ojeda¹, Y Y Acosta², J Herranz², S Martínez³, C Blanco-Aparicio³, G Criado⁴, J Pastor³, U Dianzani⁵, P Portolés⁶, J M Rojo⁷

Affiliations

¹ Unidad de Inmunología Celular, Centro Nacional de Microbiología, Instituto de Salud Carlos III, Majadahonda, Madrid, Spain.
² Departamento de Medicina Celular y Molecular, Centro de Investigaciones Biológicas, CSIC, Madrid, Spain.
³ Experimental Therapeutics Programme, Spanish National Cancer Research Centre (CNIO), Spain.
⁴ Hospital 12 de Octubre, Instituto de Investigación Hospital 12 de Octubre (I+12), E-28041 Madrid, Spain.
⁵ Interdisciplinary Research Center of Autoimmune Diseases (IRCAD) and Department of Health Sciences, University of Piemonte Orientale (UPO), Novara, Italy.
⁶ Unidad de Inmunología Celular, Centro Nacional de Microbiología, Instituto de Salud Carlos III, Majadahonda, Madrid, Spain. Electronic address: pportols@isciii.es.
⁷ Departamento de Medicina Celular y Molecular, Centro de Investigaciones Biológicas, CSIC, Madrid, Spain. Electronic address: jmrojo@cib.csic.es.

PMID: 26883061
DOI: 10.1016/j.bcp.2016.02.005

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antibodies / pharmacology
Arthritis, Experimental / drug therapy*
Arthritis, Experimental / enzymology
Arthritis, Experimental / immunology
Arthritis, Experimental / pathology
CD28 Antigens / genetics
CD28 Antigens / immunology
CD3 Complex / genetics
CD3 Complex / immunology
CD4-Positive T-Lymphocytes / drug effects*
CD4-Positive T-Lymphocytes / enzymology
CD4-Positive T-Lymphocytes / immunology
CD4-Positive T-Lymphocytes / pathology
Class Ia Phosphatidylinositol 3-Kinase / genetics
Class Ia Phosphatidylinositol 3-Kinase / immunology
Enzyme Inhibitors / pharmacology*
Extracellular Signal-Regulated MAP Kinases / genetics
Extracellular Signal-Regulated MAP Kinases / immunology
Gene Expression
Imidazoles / pharmacology*
Interferon-gamma / genetics
Interferon-gamma / immunology
Interleukin-10 / genetics
Interleukin-10 / immunology
Interleukin-2 / genetics
Interleukin-2 / immunology
Lymph Nodes / drug effects
Lymph Nodes / enzymology
Lymph Nodes / immunology
Lymph Nodes / pathology
Lymphocyte Activation / drug effects
Mice
Mice, Inbred C57BL
NFATC Transcription Factors / genetics
NFATC Transcription Factors / immunology
Phosphoinositide-3 Kinase Inhibitors*
Protein Subunits / antagonists & inhibitors*
Protein Subunits / genetics
Protein Subunits / immunology
Proto-Oncogene Proteins c-akt / genetics
Proto-Oncogene Proteins c-akt / immunology
Pyrazines / pharmacology*
T-Box Domain Proteins / genetics
T-Box Domain Proteins / immunology

Substances

Antibodies
CD28 Antigens
CD3 Complex
ETP-46321
Enzyme Inhibitors
IL10 protein, mouse
Imidazoles
Interleukin-2
NFATC Transcription Factors
Phosphoinositide-3 Kinase Inhibitors
Protein Subunits
Pyrazines
T-Box Domain Proteins
T-box transcription factor TBX21
Interleukin-10
Interferon-gamma
Class Ia Phosphatidylinositol 3-Kinase
Akt1 protein, mouse
Akt2 protein, mouse
Proto-Oncogene Proteins c-akt
Extracellular Signal-Regulated MAP Kinases