PPARγ agonist pioglitazone inhibits microglia inflammation by blocking p38 mitogen-activated protein kinase signaling pathways

The aim of this paper was to investigate the inhibitory effect of peroxisome proliferator-activated receptor-gamma (PPAR gamma) agonist pioglitazone on microglia inflammation induced by lipopolysaccharide (LPS). Highly aggressively proliferating immortalized cells were used from a rat microglial cell line. Expression of PPAR gamma, inducible NO synthase (iNOS), the p42/44 extracellular signal-regulated kinase (ERK) MAPKs, c-Jun NH2-terminal kinases (JNKs) and p38 MAPK were determined by Western blot analysis. The protein levels of tumor necrosis factor alpha (TNF-alpha), interleukin-6 (IL-6), and interleukin-1 beta (IL-1 beta) were determined by enzyme-linked immunosorbent assay. The production of nitric oxide (NO) was determined by a Nitric Oxide Assay Kit. The subcellular localization of PPAR gamma was studied by immunofluorescence microscopy analysis and nuclear-cytosolic fractionation technology, respectively. The transcriptional activity of PPAR gamma was detected by PPRE-Luciferase transcription assay. Pioglitazone effectively inhibited NO, iNOS, TNF-alpha, IL-6, IL-1 beta production in LPS-stimulated microglial cells. Additionally, pioglitazone suppressed PPAR gamma loss; enhanced transcriptional activity of PPAR gamma; and inhibited nucleus-export of PPAR gamma in microglia induced by LPS. And p38 MAPK inhibitor SB203580 had the similarity effects with pioglitazone. Signal transduction studies indicated that pioglitazone blocked the phosphorylation of p38 MAPK challenged by LPS. The results show that pioglitazone can inhibit LPS-stimulated microglia inflammation by blocking p38 MAPK signaling pathway.