A novel PPARα agonist propane-2-sulfonic acid octadec-9-enyl-amide inhibits inflammation in THP-1 cells.
Our group synthesized propane-2-sulfonic acid octadec-9-enyl-amide (N15), a novel peroxisome proliferator activated receptor alpha (PPARα) agonist. Because PPARα activation is associated with inflammation control, we hypothesize that N15 may have anti-inflammatory effects. We investigated the effect of N15 on the regulation of inflammation in THP-1 cells stimulated with lipopolysaccharide (LPS). In particular, we assessed the production of chemokines, adhesion molecules and proinflammatory cytokines, three important types of cytokines that are released from monocytes and are involved in the development of atherosclerosis. The results showed that N15 remarkably reduced the mRNA expression of chemokines, such as monocyte chemotactic protein 1 (MCP-1 or CCL2), interleukin-8 (IL-8) and interferon-inducible protein-10 (IP-10 or CXCL10), and proinflammatory cytokines, such as tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and interleukin-6 (IL-6). N15 also decreased the protein expression of vascular cell adhesion molecule (VCAM) and matrix metalloproteinase (MMP) 2 and 9. The reduction in the expression of cytokine mRNAs observed following N15 treatment was abrogated in THP-1 cells treated with PPARα siRNA, indicating that the anti-inflammatory effects of N15 are dependent on PPARα activation. Toll-like receptor 4 (TLR4)/nuclear factor-κB (NF-κB) and signal transducer and activator of transcription 3 (STAT3) inhibition, which are dependent on PPARα activation, were also involved in the mechanism underlying the anti-inflammatory effects of N15. In conclusion, the novel PPARα agonist, N15, exerts notable anti-inflammatory effects, which are mediated via PPARα activation and TLR4/NF-κB and STAT3 inhibition, in LPS-stimulated THP-1 cells. In our study, N15 exhibits promise for the treatment of atherosclerosis.
Xiamen Key Laboratory of Chiral Drugs, Medical College, Xiamen University, Xiamen 361000, China.
Yun
Y
Zhao
Xiamen Key Laboratory of Chiral Drugs, Medical College, Xiamen University, Xiamen 361000, China.
Lu
L
Yan
Xiamen Key Laboratory of Chiral Drugs, Medical College, Xiamen University, Xiamen 361000, China.
Xiu-Mei
XM
Luo
Xiamen Key Laboratory of Chiral Drugs, Medical College, Xiamen University, Xiamen 361000, China.
Lu
L
Peng
Xiamen Key Laboratory of Chiral Drugs, Medical College, Xiamen University, Xiamen 361000, China.
Han
H
Guo
Xiamen Key Laboratory of Chiral Drugs, Medical College, Xiamen University, Xiamen 361000, China.
Zuo
Z
Jing
Xiamen Key Laboratory of Chiral Drugs, Medical College, Xiamen University, Xiamen 361000, China.
Li-Chao
LC
Yang
Xiamen Key Laboratory of Chiral Drugs, Medical College, Xiamen University, Xiamen 361000, China.
Rong
R
Hu
Xiamen Key Laboratory of Chiral Drugs, Medical College, Xiamen University, Xiamen 361000, China.
Xuan
X
Wang
Zhongshan Hospital, Xiamen University, Xiamen 361000, China.
Xue-Feng
XF
Huang
Zhongshan Hospital, Xiamen University, Xiamen 361000, China. Electronic address: wang_gina@163.com.
Yi-Qing
YQ
Wang
Xiamen Key Laboratory of Chiral Drugs, Medical College, Xiamen University, Xiamen 361000, China. Electronic address: xinjin@xmu.edu.cn.
Xin
X
Jin
D000893:Anti-Inflammatory Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002470:Cell Survival / Q000187:drug effects; D018925:Chemokines / Q000378:metabolism; D011345:Fenofibrate / Q000494:pharmacology; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D008070:Lipopolysaccharides / Q000494:pharmacology; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D047493:PPAR alpha / Q000819:agonists* / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013451:Sulfonic Acids / Q000494:pharmacology* / Q000627:therapeutic use; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D019010:Vascular Cell Adhesion Molecule-1 / Q000096:biosynthesis
D000893:Anti-Inflammatory Agents; D018925:Chemokines; D008070:Lipopolysaccharides; D016328:NF-kappa B; D047493:PPAR alpha; D050796:STAT3 Transcription Factor; D013451:Sulfonic Acids; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D019010:Vascular Cell Adhesion Molecule-1; C000604189:propane-2-sulfonic acid octadec-9-enyl-amide; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D011345:Fenofibrate
Adhesion molecules; Atherosclerosis; Peroxisome proliferator activated receptor alpha; Proinflammatory cytokines; Propane-2-sulfonic acid octadec-9-enyl-amide