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Anti-inflammatory effects of α-galactosylceramide analogs in activated microglia: involvement of the p38 MAPK signaling pathway.

Jeong YH, Kim Y, Song H, Chung YS, Park SB, Kim HS - PLoS ONE (2014)

Bottom Line: Here, we designed and synthesized α-galactosylceramide (α-GalCer) analogs to exert anti-inflammatory effects in activated microglia.After identification of 4d and 4e as hit compounds, we further investigated the underlying mechanism of their anti-inflammatory effects using RT-PCR analysis.Taken together, these results suggest that p38 MAPK plays an important role in the anti-inflammatory effects of 4d and 4e via the modulation of NF-κB and AP-1 activities.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Medicine and Global Top5 Research Program, Tissue Injury Defense Research Center, Ewha Womans University Medical School, Seoul, Republic of Korea.

ABSTRACT
Microglial activation plays a pivotal role in the development and progression of neurodegenerative diseases. Thus, anti-inflammatory agents that control microglial activation can serve as potential therapeutic agents for neurodegenerative diseases. Here, we designed and synthesized α-galactosylceramide (α-GalCer) analogs to exert anti-inflammatory effects in activated microglia. We performed biological evaluations of 25 α-GalCer analogs and observed an interesting preliminary structure-activity relationship in their inhibitory influence on NO release and TNF-α production in LPS-stimulated BV2 microglial cells. After identification of 4d and 4e as hit compounds, we further investigated the underlying mechanism of their anti-inflammatory effects using RT-PCR analysis. We confirmed that 4d and 4e regulate the expression of iNOS, COX-2, IL-1β, and IL-6 at the mRNA level and the expression of TNF-α at the post-transcriptional level. In addition, both 4d and 4e inhibited LPS-induced DNA binding activities of NF-κB and AP-1 and phosphorylation of p38 MAPK without affecting other MAP kinases. When we examined the anti-inflammatory effect of a p38 MAPK-specific inhibitor, SB203580, on microglial activation, we observed an identical inhibitory pattern as that of 4d and 4e, not only on NO and TNF-α production but also on the DNA binding activities of NF-κB and AP-1. Taken together, these results suggest that p38 MAPK plays an important role in the anti-inflammatory effects of 4d and 4e via the modulation of NF-κB and AP-1 activities.

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Chemical structures of bioactive α-GalCer derivatives and newly designed α-GalCer analogs.
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pone-0087030-g001: Chemical structures of bioactive α-GalCer derivatives and newly designed α-GalCer analogs.

Mentions: Although KRN7000, a representative glycolipid of the α-GalCer family, is an excellent immunostimulatory compound, it has limited in vivo efficacy due to dual agonist effects on TH1 and TH2 cytokines. Therefore, we studied the systematic structural modification of α-GalCer to selectively polarize either the TH1 or TH2 immune response. For example, we recently described a series of α-GalCer analogs containing heterocyclic and phenyl moieties in the sphingosine backbone and found that treatment with a TH2-biased α-GalCer analog selectively stimulates the secretion of anti-inflammatory cytokines in iNKT cells (Figure 1) [25], [26]. With this selective TH2-biased α-GalCer analog in hand, we envisioned the development of new α-GalCer-based anti-inflammatory agents that control microglial activation as a potential therapy for neurodegenerative diseases. Therefore, we designed a new series of anti-inflammatory α-GalCer analogs with systematic changes in acyl chain and sphingosine backbone regions.


Anti-inflammatory effects of α-galactosylceramide analogs in activated microglia: involvement of the p38 MAPK signaling pathway.

Jeong YH, Kim Y, Song H, Chung YS, Park SB, Kim HS - PLoS ONE (2014)

Chemical structures of bioactive α-GalCer derivatives and newly designed α-GalCer analogs.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3921125&req=5

pone-0087030-g001: Chemical structures of bioactive α-GalCer derivatives and newly designed α-GalCer analogs.
Mentions: Although KRN7000, a representative glycolipid of the α-GalCer family, is an excellent immunostimulatory compound, it has limited in vivo efficacy due to dual agonist effects on TH1 and TH2 cytokines. Therefore, we studied the systematic structural modification of α-GalCer to selectively polarize either the TH1 or TH2 immune response. For example, we recently described a series of α-GalCer analogs containing heterocyclic and phenyl moieties in the sphingosine backbone and found that treatment with a TH2-biased α-GalCer analog selectively stimulates the secretion of anti-inflammatory cytokines in iNKT cells (Figure 1) [25], [26]. With this selective TH2-biased α-GalCer analog in hand, we envisioned the development of new α-GalCer-based anti-inflammatory agents that control microglial activation as a potential therapy for neurodegenerative diseases. Therefore, we designed a new series of anti-inflammatory α-GalCer analogs with systematic changes in acyl chain and sphingosine backbone regions.

Bottom Line: Here, we designed and synthesized α-galactosylceramide (α-GalCer) analogs to exert anti-inflammatory effects in activated microglia.After identification of 4d and 4e as hit compounds, we further investigated the underlying mechanism of their anti-inflammatory effects using RT-PCR analysis.Taken together, these results suggest that p38 MAPK plays an important role in the anti-inflammatory effects of 4d and 4e via the modulation of NF-κB and AP-1 activities.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Medicine and Global Top5 Research Program, Tissue Injury Defense Research Center, Ewha Womans University Medical School, Seoul, Republic of Korea.

ABSTRACT
Microglial activation plays a pivotal role in the development and progression of neurodegenerative diseases. Thus, anti-inflammatory agents that control microglial activation can serve as potential therapeutic agents for neurodegenerative diseases. Here, we designed and synthesized α-galactosylceramide (α-GalCer) analogs to exert anti-inflammatory effects in activated microglia. We performed biological evaluations of 25 α-GalCer analogs and observed an interesting preliminary structure-activity relationship in their inhibitory influence on NO release and TNF-α production in LPS-stimulated BV2 microglial cells. After identification of 4d and 4e as hit compounds, we further investigated the underlying mechanism of their anti-inflammatory effects using RT-PCR analysis. We confirmed that 4d and 4e regulate the expression of iNOS, COX-2, IL-1β, and IL-6 at the mRNA level and the expression of TNF-α at the post-transcriptional level. In addition, both 4d and 4e inhibited LPS-induced DNA binding activities of NF-κB and AP-1 and phosphorylation of p38 MAPK without affecting other MAP kinases. When we examined the anti-inflammatory effect of a p38 MAPK-specific inhibitor, SB203580, on microglial activation, we observed an identical inhibitory pattern as that of 4d and 4e, not only on NO and TNF-α production but also on the DNA binding activities of NF-κB and AP-1. Taken together, these results suggest that p38 MAPK plays an important role in the anti-inflammatory effects of 4d and 4e via the modulation of NF-κB and AP-1 activities.

Show MeSH
Related in: MedlinePlus