title: Nutrient modification of the innate immune response: a novel mechanism by which saturated fatty acids greatly amplify monocyte inflammation.
abstract: OBJECTIVE
  Monocyte/macrophage inflammation is an important contributor to diabetes and cardiovascular disease. Studies have suggested saturated fatty acids (SFA) induce monocyte inflammation in a Toll-like receptor-4-dependent manner, but recent data suggest SFA do not directly interact with Toll-like receptor-4. The present study tests the novel hypothesis that metabolism of SFA cooperatively amplifies Toll-like receptor-4-mediated inflammation.
  
  
  RESULTS
  THP-1 monocytes exposed to 100 micromol/L SFA in vitro for 16 hours followed by 1 ng/mL lipopolysaccharide demonstrated enhanced IL-6 and IL-8 mRNA and protein expression (approximately 3-fold higher than the sum of individual responses to SFA and lipopolysaccharide). SFA had similar effects on THP-1 macrophages and primary human monocytes. This amplified lipopolysaccharide response could be blocked by inhibition of SFA metabolism to ceramide and restored by cell-permeable ceramide. Both SFA and ceramide activated PKC-zeta and the mitogen-activated protein kinases Erk, JNK, and p38. Inhibition of these pathways prevented the SFA-induced increase in cytokine expression.
  
  
  CONCLUSIONS
  These results provide evidence for potent amplification of monocyte/macrophage innate immune responses by a novel pathway requiring metabolism of SFA to ceramide and activation of PKC-zeta/mitogen-activated protein kinases. These findings demonstrate how nutrient excess may modulate innate immune system activation and possibly contribute to development of diabetes and cardiovascular disease.
authors.affiliation: Phoenix VA Health Care System, 650 E. Indian School Rd, Phoenix, AZ 85012-1892, USA. Eric.Schwartz@va.gov
authors.forename: Eric A
authors.initials: EA
authors.lastname: Schwartz
authors.forename: Wei-Yang
authors.initials: WY
authors.lastname: Zhang
authors.forename: Sheetal K
authors.initials: SK
authors.lastname: Karnik
authors.forename: Sabine
authors.initials: S
authors.lastname: Borwege
authors.forename: Vijay R
authors.initials: VR
authors.lastname: Anand
authors.forename: Phyllis S
authors.initials: PS
authors.lastname: Laine
authors.forename: Yali
authors.initials: Y
authors.lastname: Su
authors.forename: Peter D
authors.initials: PD
authors.lastname: Reaven
mesh_terms: D002460:Cell Line; D002518:Ceramides / Q000378:metabolism; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects* / Q000276:immunology; D007249:Inflammation / Q000276:immunology*; D018836:Inflammation Mediators / Q000378:metabolism; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology; D009000:Monocytes / Q000187:drug effects* / Q000276:immunology; D010766:Phosphorylation; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D013997:Time Factors; D051197:Toll-Like Receptor 4 / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000099221:Protein Kinase C zeta
chemical_list: D002518:Ceramides; D048049:Extracellular Signal-Regulated MAP Kinases; D005227:Fatty Acids; D018836:Inflammation Mediators; D015850:Interleukin-6; D016209:Interleukin-8; D048031:JNK Mitogen-Activated Protein Kinases; D008070:Lipopolysaccharides; D011493:Protein Kinase C; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; D051197:Toll-Like Receptor 4; D048051:p38 Mitogen-Activated Protein Kinases; D000099221:Protein Kinase C zeta; C508606:CXCL8 protein, human; C508600:IL6 protein, human; C495345:TLR4 protein, human