A new anti-inflammatory agent KL-1037 represses proinflammatory cytokine and inducible nitric oxide synthase (iNOS) gene expression in activated microglia

Neuropharmacology
Won-Ki KimHee-Sun Kim

Abstract

Excessive proinflammatory cytokine and NO production by activated microglia play a role in neurodegenerative disorders. In this study, we found that a new compound KL-1037 suppressed LPS-induced NO release/inducible nitric oxide synthase expression in BV2 mouse microglial cells. In addition, KL-1037 prominently diminished LPS-induced production of pro-inflammatory cytokines such as TNF-alpha, IL-1 beta and IL-6, while it increased anti-inflammatory IL-10 and TGF-beta 1 production. By RNase protection assay and RT-PCR, we showed that KL-1037 regulated iNOS and cytokines at transcriptional or post-transcriptional level. Further analysis of molecular mechanisms revealed that KL-1037 prominently increased intracellular cAMP levels and potentiated LPS-induced pCREB expression. However, LPS-induced MAP kinase or NF-kappa B activities were slightly or little changed by KL-1037. Treatment with cAMP antagonist or IL-10 neutralizing antibody completely reversed upregulation of IL-10 and partially repression of TNF-alpha or NO induced by KL-1037. These data suggest that microglial inactivation by KL-1037 is at least in part due to activation of PKA pathway and/or upregulation of IL-10. Thus, repressing proinflammatory cytokines and iNOS g...Continue Reading

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Citations

Apr 7, 2010·Naunyn-Schmiedeberg's Archives of Pharmacology·Birgit KrausJörg Heilmann
Jun 2, 2009·Biological & Pharmaceutical Bulletin·Sung-Hwa SohnHyunsu Bae
Aug 12, 2005·Journal of Neurochemistry·Josep SauraJoan Serratosa
Feb 7, 2013·Biochimica Et Biophysica Acta·Ji-Sun JungHee-Sun Kim
Apr 27, 2011·Immunopharmacology and Immunotoxicology·Jun-Min LiYuan-Wu Mei
May 22, 2013·Evidence-based Complementary and Alternative Medicine : ECAM·Yeonju LeeSeikwan Oh
Apr 6, 2013·Brain Research Bulletin·Anna Rita TognaGiuseppina I Togna
Nov 11, 2015·Scientific Reports·Vito Giuseppe D'AgostinoAlessandro Provenzani
Jan 8, 2019·Journal of Neurochemistry·Kamaldeep S DhamiKathryn G Todd
May 12, 2016·Reviews in the Neurosciences·Amene SaghazadehNima Rezaei
Nov 25, 2016·Journal of Neuroinflammation·Diogo Lobo-SilvaMargarida Saraiva

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