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The Novel Therapeutic Effect of Phosphoinositide 3-Kinase-γ Inhibitor AS605240 in Autoimmune Diabetes

Type 1 diabetes (T1D) remains a major health problem worldwide, with a steadily rising incidence yet no cure. Phosphoinositide 3-kinase-γ (PI3Kγ), a member of a family of lipid kinases expressed primarily in leukocytes, has been the subject of substantial research for its role in inflammatory diseas...

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Autores principales: Azzi, Jamil, Moore, Robert F., Elyaman, Wassim, Mounayar, Marwan, El Haddad, Najib, Yang, Sunmi, Jurewicz, Mollie, Takakura, Ayumi, Petrelli, Alessandra, Fiorina, Paolo, Ruckle, Thomas, Abdi, Reza
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Diabetes Association 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3357271/
https://www.ncbi.nlm.nih.gov/pubmed/22403300
http://dx.doi.org/10.2337/db11-0134
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author Azzi, Jamil
Moore, Robert F.
Elyaman, Wassim
Mounayar, Marwan
El Haddad, Najib
Yang, Sunmi
Jurewicz, Mollie
Takakura, Ayumi
Petrelli, Alessandra
Fiorina, Paolo
Ruckle, Thomas
Abdi, Reza
author_facet Azzi, Jamil
Moore, Robert F.
Elyaman, Wassim
Mounayar, Marwan
El Haddad, Najib
Yang, Sunmi
Jurewicz, Mollie
Takakura, Ayumi
Petrelli, Alessandra
Fiorina, Paolo
Ruckle, Thomas
Abdi, Reza
author_sort Azzi, Jamil
collection PubMed
description Type 1 diabetes (T1D) remains a major health problem worldwide, with a steadily rising incidence yet no cure. Phosphoinositide 3-kinase-γ (PI3Kγ), a member of a family of lipid kinases expressed primarily in leukocytes, has been the subject of substantial research for its role in inflammatory diseases. However, the role of PI3Kγ inhibition in suppressing autoimmune T1D remains to be explored. We tested the role of the PI3Kγ inhibitor AS605240 in preventing and reversing diabetes in NOD mice and assessed the mechanisms by which this inhibition abrogates T1D. Our data indicate that the PI3Kγ pathway is highly activated in T1D. In NOD mice, we found upregulated expression of phosphorylated Akt (PAkt) in splenocytes. Notably, T regulatory cells (Tregs) showed significantly lower expression of PAkt compared with effector T cells. Inhibition of the PI3Kγ pathway by AS605240 efficiently suppressed effector T cells and induced Treg expansion through the cAMP response element-binding pathway. AS605240 effectively prevented and reversed autoimmune diabetes in NOD mice and suppressed T-cell activation and the production of inflammatory cytokines by autoreactive T cells in vitro and in vivo. These studies demonstrate the key role of the PI3Kγ pathway in determining the balance of Tregs and autoreactive cells regulating autoimmune diabetes.
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spelling pubmed-33572712013-06-01 The Novel Therapeutic Effect of Phosphoinositide 3-Kinase-γ Inhibitor AS605240 in Autoimmune Diabetes Azzi, Jamil Moore, Robert F. Elyaman, Wassim Mounayar, Marwan El Haddad, Najib Yang, Sunmi Jurewicz, Mollie Takakura, Ayumi Petrelli, Alessandra Fiorina, Paolo Ruckle, Thomas Abdi, Reza Diabetes Immunology and Transplantation Type 1 diabetes (T1D) remains a major health problem worldwide, with a steadily rising incidence yet no cure. Phosphoinositide 3-kinase-γ (PI3Kγ), a member of a family of lipid kinases expressed primarily in leukocytes, has been the subject of substantial research for its role in inflammatory diseases. However, the role of PI3Kγ inhibition in suppressing autoimmune T1D remains to be explored. We tested the role of the PI3Kγ inhibitor AS605240 in preventing and reversing diabetes in NOD mice and assessed the mechanisms by which this inhibition abrogates T1D. Our data indicate that the PI3Kγ pathway is highly activated in T1D. In NOD mice, we found upregulated expression of phosphorylated Akt (PAkt) in splenocytes. Notably, T regulatory cells (Tregs) showed significantly lower expression of PAkt compared with effector T cells. Inhibition of the PI3Kγ pathway by AS605240 efficiently suppressed effector T cells and induced Treg expansion through the cAMP response element-binding pathway. AS605240 effectively prevented and reversed autoimmune diabetes in NOD mice and suppressed T-cell activation and the production of inflammatory cytokines by autoreactive T cells in vitro and in vivo. These studies demonstrate the key role of the PI3Kγ pathway in determining the balance of Tregs and autoreactive cells regulating autoimmune diabetes. American Diabetes Association 2012-06 2012-05-14 /pmc/articles/PMC3357271/ /pubmed/22403300 http://dx.doi.org/10.2337/db11-0134 Text en © 2012 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.
spellingShingle Immunology and Transplantation
Azzi, Jamil
Moore, Robert F.
Elyaman, Wassim
Mounayar, Marwan
El Haddad, Najib
Yang, Sunmi
Jurewicz, Mollie
Takakura, Ayumi
Petrelli, Alessandra
Fiorina, Paolo
Ruckle, Thomas
Abdi, Reza
The Novel Therapeutic Effect of Phosphoinositide 3-Kinase-γ Inhibitor AS605240 in Autoimmune Diabetes
title The Novel Therapeutic Effect of Phosphoinositide 3-Kinase-γ Inhibitor AS605240 in Autoimmune Diabetes
title_full The Novel Therapeutic Effect of Phosphoinositide 3-Kinase-γ Inhibitor AS605240 in Autoimmune Diabetes
title_fullStr The Novel Therapeutic Effect of Phosphoinositide 3-Kinase-γ Inhibitor AS605240 in Autoimmune Diabetes
title_full_unstemmed The Novel Therapeutic Effect of Phosphoinositide 3-Kinase-γ Inhibitor AS605240 in Autoimmune Diabetes
title_short The Novel Therapeutic Effect of Phosphoinositide 3-Kinase-γ Inhibitor AS605240 in Autoimmune Diabetes
title_sort novel therapeutic effect of phosphoinositide 3-kinase-γ inhibitor as605240 in autoimmune diabetes
topic Immunology and Transplantation
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3357271/
https://www.ncbi.nlm.nih.gov/pubmed/22403300
http://dx.doi.org/10.2337/db11-0134
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