A novel role for protein tyrosine phosphatase 1B as a positive regulator of neuroinflammation

Gyun Jee Song, Myungsu Jung, Jong Heon Kim, Hana Park, Md Habibur Rahman, Sheng Zhang, Zhong-Yin Zhang, Dong Ho Park, Hyun Kook, In Kyu Lee, Kyoungho Suk

Research output: Contribution to journalArticle

34 Citations (Scopus)

Abstract

Background: Protein tyrosine phosphatase 1B (PTP1B) is a member of the non-transmembrane phosphotyrosine phosphatase family. Recently, PTP1B has been proposed to be a novel target of anti-cancer and anti-diabetic drugs. However, the role of PTP1B in the central nervous system is not clearly understood. Therefore, in this study, we sought to define PTP1B's role in brain inflammation. Methods: PTP1B messenger RNA (mRNA) and protein expression levels were examined in mouse brain and microglial cells after LPS treatment using RT-PCR and western blotting. Pharmacological inhibitors of PTP1B, NF-κB, and Src kinase were used to analyze these signal transduction pathways in microglia. A Griess reaction protocol was used to determine nitric oxide (NO) concentrations in primary microglia cultures and microglial cell lines. Proinflammatory cytokine production was measured by RT-PCR. Western blotting was used to assess Src phosphorylation levels. Immunostaining for Iba-1 was used to determine microglial activation in the mouse brain. Results: PTP1B expression levels were significantly increased in the brain 24 h after LPS injection, suggesting a functional role for PTP1B in brain inflammation. Microglial cells overexpressing PTP1B exhibited an enhanced production of NO and gene expression levels of TNF-α, iNOS, and IL-6 following LPS exposure, suggesting that PTP1B potentiates the microglial proinflammatory response. To confirm the role of PTP1B in neuroinflammation, we employed a highly potent and selective inhibitor of PTP1B (PTP1Bi). In LPS- or TNF-α-stimulated microglial cells, in vitro blockade of PTP1B activity using PTP1Bi markedly attenuated NO production. PTP1Bi also suppressed the expression levels of iNOS, COX-2, TNF-α, and IL-1β. PTP1B activated Src by dephosphorylating the Src protein at a negative regulatory site. PTP1B-mediated Src activation led to an enhanced proinflammatory response in the microglial cells. An intracerebroventricular injection of PTP1Bi significantly attenuated microglial activation in the hippocampus and cortex of LPS-injected mice compared to vehicle-injected mice. The gene expression levels of proinflammatory cytokines were also significantly suppressed in the brain by a PTP1Bi injection. Together, these data suggest that PTP1Bi has an anti-inflammatory effect in a mouse model of neuroinflammation. Conclusions: This study demonstrates that PTP1B is an important positive regulator of neuroinflammation and is a promising therapeutic target for neuroinflammatory and neurodegenerative diseases.

Original languageEnglish (US)
Article number86
JournalJournal of Neuroinflammation
Volume13
Issue number1
DOIs
StatePublished - 2016
Externally publishedYes

Fingerprint

Non-Receptor Type 1 Protein Tyrosine Phosphatase
Nitric Oxide
Brain
Microglia
Encephalitis
Injections
Western Blotting
Cytokines
Gene Expression
Polymerase Chain Reaction
Protein Tyrosine Phosphatases
src-Family Kinases

Keywords

  • Lipopolysaccharide
  • Microglia
  • Neuroinflammation
  • Proinflammatory cytokines
  • PTP1B
  • Src

ASJC Scopus subject areas

  • Neuroscience(all)
  • Immunology
  • Neurology
  • Cellular and Molecular Neuroscience

Cite this

Song, G. J., Jung, M., Kim, J. H., Park, H., Rahman, M. H., Zhang, S., ... Suk, K. (2016). A novel role for protein tyrosine phosphatase 1B as a positive regulator of neuroinflammation. Journal of Neuroinflammation, 13(1), [86]. https://doi.org/10.1186/s12974-016-0545-3

A novel role for protein tyrosine phosphatase 1B as a positive regulator of neuroinflammation. / Song, Gyun Jee; Jung, Myungsu; Kim, Jong Heon; Park, Hana; Rahman, Md Habibur; Zhang, Sheng; Zhang, Zhong-Yin; Park, Dong Ho; Kook, Hyun; Lee, In Kyu; Suk, Kyoungho.

In: Journal of Neuroinflammation, Vol. 13, No. 1, 86, 2016.

Research output: Contribution to journalArticle

Song, GJ, Jung, M, Kim, JH, Park, H, Rahman, MH, Zhang, S, Zhang, Z-Y, Park, DH, Kook, H, Lee, IK & Suk, K 2016, 'A novel role for protein tyrosine phosphatase 1B as a positive regulator of neuroinflammation', Journal of Neuroinflammation, vol. 13, no. 1, 86. https://doi.org/10.1186/s12974-016-0545-3
Song, Gyun Jee ; Jung, Myungsu ; Kim, Jong Heon ; Park, Hana ; Rahman, Md Habibur ; Zhang, Sheng ; Zhang, Zhong-Yin ; Park, Dong Ho ; Kook, Hyun ; Lee, In Kyu ; Suk, Kyoungho. / A novel role for protein tyrosine phosphatase 1B as a positive regulator of neuroinflammation. In: Journal of Neuroinflammation. 2016 ; Vol. 13, No. 1.
@article{01f9428cfeed4f469dc2b35183766f87,
title = "A novel role for protein tyrosine phosphatase 1B as a positive regulator of neuroinflammation",
abstract = "Background: Protein tyrosine phosphatase 1B (PTP1B) is a member of the non-transmembrane phosphotyrosine phosphatase family. Recently, PTP1B has been proposed to be a novel target of anti-cancer and anti-diabetic drugs. However, the role of PTP1B in the central nervous system is not clearly understood. Therefore, in this study, we sought to define PTP1B's role in brain inflammation. Methods: PTP1B messenger RNA (mRNA) and protein expression levels were examined in mouse brain and microglial cells after LPS treatment using RT-PCR and western blotting. Pharmacological inhibitors of PTP1B, NF-κB, and Src kinase were used to analyze these signal transduction pathways in microglia. A Griess reaction protocol was used to determine nitric oxide (NO) concentrations in primary microglia cultures and microglial cell lines. Proinflammatory cytokine production was measured by RT-PCR. Western blotting was used to assess Src phosphorylation levels. Immunostaining for Iba-1 was used to determine microglial activation in the mouse brain. Results: PTP1B expression levels were significantly increased in the brain 24 h after LPS injection, suggesting a functional role for PTP1B in brain inflammation. Microglial cells overexpressing PTP1B exhibited an enhanced production of NO and gene expression levels of TNF-α, iNOS, and IL-6 following LPS exposure, suggesting that PTP1B potentiates the microglial proinflammatory response. To confirm the role of PTP1B in neuroinflammation, we employed a highly potent and selective inhibitor of PTP1B (PTP1Bi). In LPS- or TNF-α-stimulated microglial cells, in vitro blockade of PTP1B activity using PTP1Bi markedly attenuated NO production. PTP1Bi also suppressed the expression levels of iNOS, COX-2, TNF-α, and IL-1β. PTP1B activated Src by dephosphorylating the Src protein at a negative regulatory site. PTP1B-mediated Src activation led to an enhanced proinflammatory response in the microglial cells. An intracerebroventricular injection of PTP1Bi significantly attenuated microglial activation in the hippocampus and cortex of LPS-injected mice compared to vehicle-injected mice. The gene expression levels of proinflammatory cytokines were also significantly suppressed in the brain by a PTP1Bi injection. Together, these data suggest that PTP1Bi has an anti-inflammatory effect in a mouse model of neuroinflammation. Conclusions: This study demonstrates that PTP1B is an important positive regulator of neuroinflammation and is a promising therapeutic target for neuroinflammatory and neurodegenerative diseases.",
keywords = "Lipopolysaccharide, Microglia, Neuroinflammation, Proinflammatory cytokines, PTP1B, Src",
author = "Song, {Gyun Jee} and Myungsu Jung and Kim, {Jong Heon} and Hana Park and Rahman, {Md Habibur} and Sheng Zhang and Zhong-Yin Zhang and Park, {Dong Ho} and Hyun Kook and Lee, {In Kyu} and Kyoungho Suk",
year = "2016",
doi = "10.1186/s12974-016-0545-3",
language = "English (US)",
volume = "13",
journal = "Journal of Neuroinflammation",
issn = "1742-2094",
publisher = "BioMed Central",
number = "1",

}

TY - JOUR

T1 - A novel role for protein tyrosine phosphatase 1B as a positive regulator of neuroinflammation

AU - Song, Gyun Jee

AU - Jung, Myungsu

AU - Kim, Jong Heon

AU - Park, Hana

AU - Rahman, Md Habibur

AU - Zhang, Sheng

AU - Zhang, Zhong-Yin

AU - Park, Dong Ho

AU - Kook, Hyun

AU - Lee, In Kyu

AU - Suk, Kyoungho

PY - 2016

Y1 - 2016

N2 - Background: Protein tyrosine phosphatase 1B (PTP1B) is a member of the non-transmembrane phosphotyrosine phosphatase family. Recently, PTP1B has been proposed to be a novel target of anti-cancer and anti-diabetic drugs. However, the role of PTP1B in the central nervous system is not clearly understood. Therefore, in this study, we sought to define PTP1B's role in brain inflammation. Methods: PTP1B messenger RNA (mRNA) and protein expression levels were examined in mouse brain and microglial cells after LPS treatment using RT-PCR and western blotting. Pharmacological inhibitors of PTP1B, NF-κB, and Src kinase were used to analyze these signal transduction pathways in microglia. A Griess reaction protocol was used to determine nitric oxide (NO) concentrations in primary microglia cultures and microglial cell lines. Proinflammatory cytokine production was measured by RT-PCR. Western blotting was used to assess Src phosphorylation levels. Immunostaining for Iba-1 was used to determine microglial activation in the mouse brain. Results: PTP1B expression levels were significantly increased in the brain 24 h after LPS injection, suggesting a functional role for PTP1B in brain inflammation. Microglial cells overexpressing PTP1B exhibited an enhanced production of NO and gene expression levels of TNF-α, iNOS, and IL-6 following LPS exposure, suggesting that PTP1B potentiates the microglial proinflammatory response. To confirm the role of PTP1B in neuroinflammation, we employed a highly potent and selective inhibitor of PTP1B (PTP1Bi). In LPS- or TNF-α-stimulated microglial cells, in vitro blockade of PTP1B activity using PTP1Bi markedly attenuated NO production. PTP1Bi also suppressed the expression levels of iNOS, COX-2, TNF-α, and IL-1β. PTP1B activated Src by dephosphorylating the Src protein at a negative regulatory site. PTP1B-mediated Src activation led to an enhanced proinflammatory response in the microglial cells. An intracerebroventricular injection of PTP1Bi significantly attenuated microglial activation in the hippocampus and cortex of LPS-injected mice compared to vehicle-injected mice. The gene expression levels of proinflammatory cytokines were also significantly suppressed in the brain by a PTP1Bi injection. Together, these data suggest that PTP1Bi has an anti-inflammatory effect in a mouse model of neuroinflammation. Conclusions: This study demonstrates that PTP1B is an important positive regulator of neuroinflammation and is a promising therapeutic target for neuroinflammatory and neurodegenerative diseases.

AB - Background: Protein tyrosine phosphatase 1B (PTP1B) is a member of the non-transmembrane phosphotyrosine phosphatase family. Recently, PTP1B has been proposed to be a novel target of anti-cancer and anti-diabetic drugs. However, the role of PTP1B in the central nervous system is not clearly understood. Therefore, in this study, we sought to define PTP1B's role in brain inflammation. Methods: PTP1B messenger RNA (mRNA) and protein expression levels were examined in mouse brain and microglial cells after LPS treatment using RT-PCR and western blotting. Pharmacological inhibitors of PTP1B, NF-κB, and Src kinase were used to analyze these signal transduction pathways in microglia. A Griess reaction protocol was used to determine nitric oxide (NO) concentrations in primary microglia cultures and microglial cell lines. Proinflammatory cytokine production was measured by RT-PCR. Western blotting was used to assess Src phosphorylation levels. Immunostaining for Iba-1 was used to determine microglial activation in the mouse brain. Results: PTP1B expression levels were significantly increased in the brain 24 h after LPS injection, suggesting a functional role for PTP1B in brain inflammation. Microglial cells overexpressing PTP1B exhibited an enhanced production of NO and gene expression levels of TNF-α, iNOS, and IL-6 following LPS exposure, suggesting that PTP1B potentiates the microglial proinflammatory response. To confirm the role of PTP1B in neuroinflammation, we employed a highly potent and selective inhibitor of PTP1B (PTP1Bi). In LPS- or TNF-α-stimulated microglial cells, in vitro blockade of PTP1B activity using PTP1Bi markedly attenuated NO production. PTP1Bi also suppressed the expression levels of iNOS, COX-2, TNF-α, and IL-1β. PTP1B activated Src by dephosphorylating the Src protein at a negative regulatory site. PTP1B-mediated Src activation led to an enhanced proinflammatory response in the microglial cells. An intracerebroventricular injection of PTP1Bi significantly attenuated microglial activation in the hippocampus and cortex of LPS-injected mice compared to vehicle-injected mice. The gene expression levels of proinflammatory cytokines were also significantly suppressed in the brain by a PTP1Bi injection. Together, these data suggest that PTP1Bi has an anti-inflammatory effect in a mouse model of neuroinflammation. Conclusions: This study demonstrates that PTP1B is an important positive regulator of neuroinflammation and is a promising therapeutic target for neuroinflammatory and neurodegenerative diseases.

KW - Lipopolysaccharide

KW - Microglia

KW - Neuroinflammation

KW - Proinflammatory cytokines

KW - PTP1B

KW - Src

UR - http://www.scopus.com/inward/record.url?scp=85007460170&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85007460170&partnerID=8YFLogxK

U2 - 10.1186/s12974-016-0545-3

DO - 10.1186/s12974-016-0545-3

M3 - Article

C2 - 27095436

AN - SCOPUS:85007460170

VL - 13

JO - Journal of Neuroinflammation

JF - Journal of Neuroinflammation

SN - 1742-2094

IS - 1

M1 - 86

ER -