15-Deoxy-Δ12,14-prostaglandin J2 modulates manganese-induced activation of the NF-κB, Nrf2, and PI3K pathways in astrocytes

Eunsook Lee, Zhaobao Yin, Marta Sidoryk-Wȩgrzynowicz, Haiyan Jiang, Michael Aschner

Research output: Contribution to journalArticle

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Abstract

Excessive exposure to manganese (Mn) increases levels of oxidative stressors and proinflammatory mediators, such as cyclooxygenase-2 and prostaglandin E2. Mn also activates nuclear factor-κB (NF-κB), an important mediator of inflammation. The signaling molecule 15-deoxy-Δ12,14-prostaglandin J2 (15 d-PGJ2) is an anti-inflammatory prostaglandin. Here, we tested the hypothesis that 15 d-PGJ2 modulates Mn-induced activation of astrocytic intracellular signaling, including NF-κB and nuclear factor erythroid 2-related factor (Nrf2), a master regulator of antioxidant transcriptional responses. The results establish that 15 d-PGJ2 suppresses Mn-induced NF-κB activation by interacting with several signaling pathways. The PI3K/Akt pathway, which is upstream of NF-κB, plays a role in this activation, because (i) pretreatment with 15 d-PGJ2 (10 μM for 1 h) significantly (p < 0.01) inhibited Mn (500 μM)-induced PI3K/Akt activation and (ii) inhibition of the PI3K/Akt pathway with LY29004 significantly (p < 0.05) decreased NF-κB activation. 15 d-PGJ2 also significantly (p < 0.05) attenuated Mn-induced astrocytic NF-κB activation by inhibiting the Mn-induced phosphorylation of IκB kinase and subsequent IκB-α degradation. Because Mn-induced oxidative stress is also associated with Nrf2 activation, additional studies addressed the ability of 15 d-PGJ2 to modulate the Nrf2 pathway. 15 d-PGJ2 significantly (p < 0.01) increased Nrf2 expression in whole-cell lysates. Consistent with its pro-oxidant properties, Mn also increased Nrf2 expression. Nevertheless, cotreatment of whole-cell lysates with both Mn and 15 d-PGJ2 partially suppressed (p < 0.01) the 15 d-PGJ2-induced increase in astrocytic Nrf2 protein expression. Mn treatment also decreased (p < 0.001) expression of DJ-1, a Parkinson disease-associated protein and a stabilizer of Nrf2, and 15 d-PGJ 2 attenuated Mn-induced astrocytic inhibition of DJ-1 expression. Collectively, these results demonstrate that 15 d-PGJ2 exerts a protective effect in astrocytes against Mn-induced inflammation and oxidative stress by modulating the activation of the NF-κB and Nrf2 signaling pathways.

Original languageEnglish (US)
Pages (from-to)1067-1074
Number of pages8
JournalFree Radical Biology and Medicine
Volume52
Issue number6
DOIs
StatePublished - Mar 15 2012
Externally publishedYes

Fingerprint

Manganese
Phosphatidylinositol 3-Kinases
Astrocytes
Chemical activation
Oxidative stress
15-deoxy-delta(12,14)-prostaglandin J2
Oxidative Stress
Inflammation Mediators
Phosphorylation
Cyclooxygenase 2
Dinoprostone
Prostaglandins
Reactive Oxygen Species
Proteins
Anti-Inflammatory Agents
Phosphotransferases
Antioxidants
Inflammation

Keywords

  • 15 d-PGJ
  • Free radicals
  • Manganese
  • Neurotoxicity
  • NF-κB
  • Nrf2

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)

Cite this

15-Deoxy-Δ12,14-prostaglandin J2 modulates manganese-induced activation of the NF-κB, Nrf2, and PI3K pathways in astrocytes. / Lee, Eunsook; Yin, Zhaobao; Sidoryk-Wȩgrzynowicz, Marta; Jiang, Haiyan; Aschner, Michael.

In: Free Radical Biology and Medicine, Vol. 52, No. 6, 15.03.2012, p. 1067-1074.

Research output: Contribution to journalArticle

Lee, Eunsook ; Yin, Zhaobao ; Sidoryk-Wȩgrzynowicz, Marta ; Jiang, Haiyan ; Aschner, Michael. / 15-Deoxy-Δ12,14-prostaglandin J2 modulates manganese-induced activation of the NF-κB, Nrf2, and PI3K pathways in astrocytes. In: Free Radical Biology and Medicine. 2012 ; Vol. 52, No. 6. pp. 1067-1074.
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abstract = "Excessive exposure to manganese (Mn) increases levels of oxidative stressors and proinflammatory mediators, such as cyclooxygenase-2 and prostaglandin E2. Mn also activates nuclear factor-κB (NF-κB), an important mediator of inflammation. The signaling molecule 15-deoxy-Δ12,14-prostaglandin J2 (15 d-PGJ2) is an anti-inflammatory prostaglandin. Here, we tested the hypothesis that 15 d-PGJ2 modulates Mn-induced activation of astrocytic intracellular signaling, including NF-κB and nuclear factor erythroid 2-related factor (Nrf2), a master regulator of antioxidant transcriptional responses. The results establish that 15 d-PGJ2 suppresses Mn-induced NF-κB activation by interacting with several signaling pathways. The PI3K/Akt pathway, which is upstream of NF-κB, plays a role in this activation, because (i) pretreatment with 15 d-PGJ2 (10 μM for 1 h) significantly (p < 0.01) inhibited Mn (500 μM)-induced PI3K/Akt activation and (ii) inhibition of the PI3K/Akt pathway with LY29004 significantly (p < 0.05) decreased NF-κB activation. 15 d-PGJ2 also significantly (p < 0.05) attenuated Mn-induced astrocytic NF-κB activation by inhibiting the Mn-induced phosphorylation of IκB kinase and subsequent IκB-α degradation. Because Mn-induced oxidative stress is also associated with Nrf2 activation, additional studies addressed the ability of 15 d-PGJ2 to modulate the Nrf2 pathway. 15 d-PGJ2 significantly (p < 0.01) increased Nrf2 expression in whole-cell lysates. Consistent with its pro-oxidant properties, Mn also increased Nrf2 expression. Nevertheless, cotreatment of whole-cell lysates with both Mn and 15 d-PGJ2 partially suppressed (p < 0.01) the 15 d-PGJ2-induced increase in astrocytic Nrf2 protein expression. Mn treatment also decreased (p < 0.001) expression of DJ-1, a Parkinson disease-associated protein and a stabilizer of Nrf2, and 15 d-PGJ 2 attenuated Mn-induced astrocytic inhibition of DJ-1 expression. Collectively, these results demonstrate that 15 d-PGJ2 exerts a protective effect in astrocytes against Mn-induced inflammation and oxidative stress by modulating the activation of the NF-κB and Nrf2 signaling pathways.",
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N2 - Excessive exposure to manganese (Mn) increases levels of oxidative stressors and proinflammatory mediators, such as cyclooxygenase-2 and prostaglandin E2. Mn also activates nuclear factor-κB (NF-κB), an important mediator of inflammation. The signaling molecule 15-deoxy-Δ12,14-prostaglandin J2 (15 d-PGJ2) is an anti-inflammatory prostaglandin. Here, we tested the hypothesis that 15 d-PGJ2 modulates Mn-induced activation of astrocytic intracellular signaling, including NF-κB and nuclear factor erythroid 2-related factor (Nrf2), a master regulator of antioxidant transcriptional responses. The results establish that 15 d-PGJ2 suppresses Mn-induced NF-κB activation by interacting with several signaling pathways. The PI3K/Akt pathway, which is upstream of NF-κB, plays a role in this activation, because (i) pretreatment with 15 d-PGJ2 (10 μM for 1 h) significantly (p < 0.01) inhibited Mn (500 μM)-induced PI3K/Akt activation and (ii) inhibition of the PI3K/Akt pathway with LY29004 significantly (p < 0.05) decreased NF-κB activation. 15 d-PGJ2 also significantly (p < 0.05) attenuated Mn-induced astrocytic NF-κB activation by inhibiting the Mn-induced phosphorylation of IκB kinase and subsequent IκB-α degradation. Because Mn-induced oxidative stress is also associated with Nrf2 activation, additional studies addressed the ability of 15 d-PGJ2 to modulate the Nrf2 pathway. 15 d-PGJ2 significantly (p < 0.01) increased Nrf2 expression in whole-cell lysates. Consistent with its pro-oxidant properties, Mn also increased Nrf2 expression. Nevertheless, cotreatment of whole-cell lysates with both Mn and 15 d-PGJ2 partially suppressed (p < 0.01) the 15 d-PGJ2-induced increase in astrocytic Nrf2 protein expression. Mn treatment also decreased (p < 0.001) expression of DJ-1, a Parkinson disease-associated protein and a stabilizer of Nrf2, and 15 d-PGJ 2 attenuated Mn-induced astrocytic inhibition of DJ-1 expression. Collectively, these results demonstrate that 15 d-PGJ2 exerts a protective effect in astrocytes against Mn-induced inflammation and oxidative stress by modulating the activation of the NF-κB and Nrf2 signaling pathways.

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