PPARγ agonist pioglitazone inhibits microglia inflammation by blocking p38 mitogen-activated protein kinase signaling pathways.
OBJECTIVE
The aim of this paper was to investigate the inhibitory effect of peroxisome proliferator-activated receptor-gamma (PPARγ) agonist pioglitazone on microglia inflammation induced by lipopolysaccharide (LPS).


METHODS
Highly aggressively proliferating immortalized cells were used from a rat microglial cell line. Expression of PPARγ, 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 α (TNF-α), interleukin-6 (IL-6), and interleukin-1β (IL-1β) 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 PPARγ was studied by immunofluorescence microscopy analysis and nuclear-cytosolic fractionation technology, respectively. The transcriptional activity of PPARγ was detected by PPRE-Luciferase transcription assay.


RESULTS
Pioglitazone effectively inhibited NO, iNOS, TNF-α, IL-6, IL-1β production in LPS-stimulated microglial cells. Additionally, pioglitazone suppressed PPARγ loss; enhanced transcriptional activity of PPARγ; and inhibited nucleus-export of PPARγ 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.


CONCLUSIONS
The results show that pioglitazone can inhibit LPS-stimulated microglia inflammation by blocking p38 MAPK signaling pathway.
Ji
Huoyan
H
Laboratory Center, Affiliated Hospital of Nantong University, Nantong, China.
Wang
Huimin
H
Zhang
Fupeng
F
Li
Xiaohong
X
Xiang
Lu
L
Aiguo
Shen
S
D000818:Animals; D002460:Cell Line; D016207:Cytokines / Q000276:immunology; D007004:Hypoglycemic Agents / Q000494:pharmacology / Q000627:therapeutic use; D007249:Inflammation / Q000188:drug therapy*; D053583:Interleukin-1beta / Q000096:biosynthesis; D015850:Interleukin-6 / Q000096:biosynthesis; D008070:Lipopolysaccharides / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D017628:Microglia / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D047495:PPAR gamma / Q000819:agonists* / Q000378:metabolism; D000077205:Pioglitazone; D051381:Rats; D045162:Thiazolidinediones / Q000494:pharmacology / Q000627:therapeutic use; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*
D016207:Cytokines; D007004:Hypoglycemic Agents; D053583:Interleukin-1beta; D015850:Interleukin-6; D008070:Lipopolysaccharides; D047495:PPAR gamma; D045162:Thiazolidinediones; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; D048051:p38 Mitogen-Activated Protein Kinases; D000077205:Pioglitazone