title: 15-Deoxy-Δ12,14-prostaglandin J₂ modulates manganese-induced activation of the NF-κB, Nrf2, and PI3K pathways in astrocytes.
abstract: Excessive exposure to manganese (Mn) increases levels of oxidative stressors and proinflammatory mediators, such as cyclooxygenase-2 and prostaglandin E(2). Mn also activates nuclear factor-κB (NF-κB), an important mediator of inflammation. The signaling molecule 15-deoxy-Δ12,14-prostaglandin J(2) (15 d-PGJ(2)) is an anti-inflammatory prostaglandin. Here, we tested the hypothesis that 15 d-PGJ(2) 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-PGJ(2) 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-PGJ(2) (10 μM for 1h) 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-PGJ(2) 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-PGJ(2) to modulate the Nrf2 pathway. 15 d-PGJ(2) 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-PGJ(2) partially suppressed (p<0.01) the 15 d-PGJ(2)-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 15d-PGJ(2) 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.
authors.affiliation: Department of Physiology, Meharry Medical College, Nashville, TN 37208, USA.
authors.forename: Eunsook
authors.initials: E
authors.lastname: Lee
authors.forename: Zhaobao
authors.initials: Z
authors.lastname: Yin
authors.forename: Marta
authors.initials: M
authors.lastname: Sidoryk-Węgrzynowicz
authors.forename: Haiyan
authors.initials: H
authors.lastname: Jiang
authors.forename: Michael
authors.initials: M
authors.lastname: Aschner
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D002867:Chromones / Q000494:pharmacology; D019610:Cytoprotection / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008345:Manganese / Q000378:metabolism; D009025:Morpholines / Q000494:pharmacology; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D010300:Parkinson Disease / Q000188:drug therapy / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000494:pharmacology; D000071617:Protein Deglycase DJ-1; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D015533:Transcriptional Activation / Q000187:drug effects
chemical_list: C097240:15-deoxy-delta(12,14)-prostaglandin J2; D002867:Chromones; D047908:Intracellular Signaling Peptides and Proteins; C549075:LY 290042; D009025:Morpholines; D051267:NF-E2-Related Factor 2; D016328:NF-kappa B; D015513:Oncogene Proteins; D000081082:Phosphoinositide-3 Kinase Inhibitors; D008345:Manganese; C105131:PARK7 protein, human; D000071617:Protein Deglycase DJ-1; D015230:Prostaglandin D2