Zaprinast activates MAPKs, NFκB, and Akt and induces the expressions of inflammatory genes in microglia

International Immunopharmacology
Heung-Soon LeeSang-Hyun Choi

Abstract

Previously, the authors reported that zaprinast, an inhibitor of cGMP-selective phosphodiesterases, induced the secretions of TNF-α and IL-1β by microglia and enhanced the induction of iNOS by lipopolysaccharide (LPS). In this study, the signaling mechanism responsible for microglial activation by zaprinast was investigated and the effects of zaprinast and LPS on microglial activation were compared. Zaprinast was found to activate ERK1/2, p38 MAPK, JNK, NFκB, and PI3K/Akt, and subsequently, induce the mRNA expressions of IL-1α, IL-1β, TNF-α, CCL2, CCL4, CXCL1, CXCL2, and CD14. Associations between signaling pathways and gene expressions were examined by treating microglia with signal inhibitors. PDTC inhibited the induction of all the above genes by zaprinast, and SB203580 inhibited all genes except CXCL1. SP600125, PD98059, and LY294002 inhibited the induction of at least CCL2. Microglial activation by zaprinast was then compared with full-blown activation by LPS. The zaprinast-induced phosphorylations of MAPKs and IκB were less prompt than LPS-induced phosphorylations. IκB degradation by LPS was significant at 10min and did not return to normal, whereas zaprinast induced a later, transient degradation. LPS induced the mRNA ex...Continue Reading

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Citations

Sep 26, 2015·Brain Research·Ana Karolina Santana NunesChristina Alves Peixoto
Dec 17, 2014·European Journal of Clinical Investigation·Susana Martin-RodriguezMaribel Diaz-Ricart
Oct 6, 2015·Biochemical and Biophysical Research Communications·Ji-Eun HamSang-Hyun Choi

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