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Vascular Endothelial Growth Factor Receptor Inhibitor SU5416 Suppresses Lymphocyte Generation and Immune Responses in Mice by Increasing Plasma Corticosterone

Inhibitors of vascular endothelial growth factor and its receptors (VEGFRs) are attractive therapeutic candidates for cancer treatment. One such small molecule VEGFR inhibitor, SU5416, limits angiogenesis in vivo and is widely used for investigating VEGFR signaling in tumor pathophysiology. Herein,...

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Autores principales: Grailer, Jamison J., Steeber, Douglas A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3774642/
https://www.ncbi.nlm.nih.gov/pubmed/24066177
http://dx.doi.org/10.1371/journal.pone.0075390
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author Grailer, Jamison J.
Steeber, Douglas A.
author_facet Grailer, Jamison J.
Steeber, Douglas A.
author_sort Grailer, Jamison J.
collection PubMed
description Inhibitors of vascular endothelial growth factor and its receptors (VEGFRs) are attractive therapeutic candidates for cancer treatment. One such small molecule VEGFR inhibitor, SU5416, limits angiogenesis in vivo and is widely used for investigating VEGFR signaling in tumor pathophysiology. Herein, we describe novel actions of SU5416 on the immune system. Treatment of mice with SU5416 for 3 days induced significant reductions in size and cellularity of peripheral lymph nodes. Interestingly, SU5416 did not affect initial lymphocyte localization to peripheral lymph nodes but did reduce lymphocyte accumulation during long-term migration assays. Treatment with SU5416 also induced severe loss of double-positive thymocytes resulting in thymic atrophy and a reduction in peripheral B cells. Furthermore, immune responses following immunization were reduced in mice treated with SU5416. Findings of thymic atrophy and reduced weight gain during SU5416 treatment suggested elevated corticosterone levels. Indeed, a significant 5-fold increase in serum corticosterone was found 4 hours after treatment with SU5416. Importantly, adrenalectomy negated the effects of SU5416 treatment on primary immune tissues, and partial reversal of SU5416-induced changes was observed following blockade of glucocorticoid receptors. SU5416 has been reported to inhibit the activation of latent transforming growth factor (TGF)-β, a cytokine involved in the regulation of glucocorticoid release by the adrenal glands. Interestingly, treatment with a TGF-β receptor inhibitor, showed a similar phenotype as SU5416 treatment, including elevated serum corticosterone levels and thymic atrophy. Therefore, these results suggest that SU5416 induces glucocorticoid release directly from the adrenal glands, possibly by inhibition of TGF-β activation.
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spelling pubmed-37746422013-09-24 Vascular Endothelial Growth Factor Receptor Inhibitor SU5416 Suppresses Lymphocyte Generation and Immune Responses in Mice by Increasing Plasma Corticosterone Grailer, Jamison J. Steeber, Douglas A. PLoS One Research Article Inhibitors of vascular endothelial growth factor and its receptors (VEGFRs) are attractive therapeutic candidates for cancer treatment. One such small molecule VEGFR inhibitor, SU5416, limits angiogenesis in vivo and is widely used for investigating VEGFR signaling in tumor pathophysiology. Herein, we describe novel actions of SU5416 on the immune system. Treatment of mice with SU5416 for 3 days induced significant reductions in size and cellularity of peripheral lymph nodes. Interestingly, SU5416 did not affect initial lymphocyte localization to peripheral lymph nodes but did reduce lymphocyte accumulation during long-term migration assays. Treatment with SU5416 also induced severe loss of double-positive thymocytes resulting in thymic atrophy and a reduction in peripheral B cells. Furthermore, immune responses following immunization were reduced in mice treated with SU5416. Findings of thymic atrophy and reduced weight gain during SU5416 treatment suggested elevated corticosterone levels. Indeed, a significant 5-fold increase in serum corticosterone was found 4 hours after treatment with SU5416. Importantly, adrenalectomy negated the effects of SU5416 treatment on primary immune tissues, and partial reversal of SU5416-induced changes was observed following blockade of glucocorticoid receptors. SU5416 has been reported to inhibit the activation of latent transforming growth factor (TGF)-β, a cytokine involved in the regulation of glucocorticoid release by the adrenal glands. Interestingly, treatment with a TGF-β receptor inhibitor, showed a similar phenotype as SU5416 treatment, including elevated serum corticosterone levels and thymic atrophy. Therefore, these results suggest that SU5416 induces glucocorticoid release directly from the adrenal glands, possibly by inhibition of TGF-β activation. Public Library of Science 2013-09-16 /pmc/articles/PMC3774642/ /pubmed/24066177 http://dx.doi.org/10.1371/journal.pone.0075390 Text en © 2013 Grailer, Steeber http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Grailer, Jamison J.
Steeber, Douglas A.
Vascular Endothelial Growth Factor Receptor Inhibitor SU5416 Suppresses Lymphocyte Generation and Immune Responses in Mice by Increasing Plasma Corticosterone
title Vascular Endothelial Growth Factor Receptor Inhibitor SU5416 Suppresses Lymphocyte Generation and Immune Responses in Mice by Increasing Plasma Corticosterone
title_full Vascular Endothelial Growth Factor Receptor Inhibitor SU5416 Suppresses Lymphocyte Generation and Immune Responses in Mice by Increasing Plasma Corticosterone
title_fullStr Vascular Endothelial Growth Factor Receptor Inhibitor SU5416 Suppresses Lymphocyte Generation and Immune Responses in Mice by Increasing Plasma Corticosterone
title_full_unstemmed Vascular Endothelial Growth Factor Receptor Inhibitor SU5416 Suppresses Lymphocyte Generation and Immune Responses in Mice by Increasing Plasma Corticosterone
title_short Vascular Endothelial Growth Factor Receptor Inhibitor SU5416 Suppresses Lymphocyte Generation and Immune Responses in Mice by Increasing Plasma Corticosterone
title_sort vascular endothelial growth factor receptor inhibitor su5416 suppresses lymphocyte generation and immune responses in mice by increasing plasma corticosterone
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3774642/
https://www.ncbi.nlm.nih.gov/pubmed/24066177
http://dx.doi.org/10.1371/journal.pone.0075390
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