Fenretinide corrects the imbalance between omega-6 to omega-3 polyunsaturated fatty acids and inhibits macrophage inflammatory mediators via the ERK pathway.
We previously identified Fragile X-related protein 1 (FXR1) as an RNA-binding protein involved in the post-transcriptional control of TNF and other cytokines in macrophages. Macrophages derived from FXR1-KO mice overexpress several inflammatory cytokines including TNF. Recently, we showed that fenretinide (4HPR) is able to inhibit several inflammatory cytokines in the lungs of cystic fibrosis mice, which also have abnormal immune responses. Therefore, we hypothesized that 4HPR might also be able to downregulate excessive inflammation even in macrophages with ablated FXR1. Indeed, our results demonstrate that 4HPR inhibited the excessive production of inflammatory mediators, including TNF, IL-6, CCL2 and CCL-5 in LPS-stimulated FXR1-KO macrophages, by selectively inhibiting phosphorylation of ERK1/2, which is naturally more phosphorylated in FXR1-KO cells. We also found that LPS stimulation of FXR1-KO macrophages led to significantly higher ratio of arachidonic acid/docosahexaenoic acid than observed in FXR1-WT macrophages. Interestingly, treatment with 4HPR was associated with the normalization of arachidonic acid/docosahexaenoic acid ratio in macrophages, which we found to impact phosphorylation of ERK1/2. Overall, this study shows for the first time that 4HPR modulates inflammatory cytokine expression in macrophages by correcting a phospholipid-bound fatty acid imbalance that impacts the phosphorylation of ERK1/2.
McGill University, Department of Medicine and Department of Human Genetics, McGill University Health Center Research Institute, Montreal, Quebec, Canada.
Claude
C
Lachance
Gabriella
G
Wojewodka
Tom A A
TA
Skinner
Claudine
C
Guilbault
Juan B
JB
De Sanctis
Danuta
D
Radzioch
D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D002460:Cell Line; D004281:Docosahexaenoic Acids / Q000378:metabolism; D015525:Fatty Acids, Omega-3 / Q000378:metabolism*; D043371:Fatty Acids, Omega-6 / Q000378:metabolism*; D017313:Fenretinide / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D055786:Gene Knockout Techniques; D018836:Inflammation Mediators / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000276:immunology; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010766:Phosphorylation; D020871:RNA Stability / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics; D048069:Tumor Necrosis Factors / Q000235:genetics / Q000378:metabolism
D015525:Fatty Acids, Omega-3; D043371:Fatty Acids, Omega-6; C496283:Fxr1h protein, mouse; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D048069:Tumor Necrosis Factors; D017313:Fenretinide; D004281:Docosahexaenoic Acids; D016718:Arachidonic Acid; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3