Regulation of beta-amyloid stimulated proinflammatory responses by peroxisome proliferator-activated receptor alpha.
Amyloid deposition within the brains of Alzheimer's Disease patients results in the activation of microglial cells and the induction of a local inflammatory response. The interaction of microglia or monocytes with beta-amyloid (A beta) fibrils elicits the activation a complex tyrosine kinase-based signal transduction cascade leading to stimulation of multiple independent signaling pathways and ultimately to changes in proinflammatory gene expression. The A beta-stimulated expression of proinflammatory genes in myeloid lineage cells is antagonized by the action of a family of ligand-activated nuclear hormone receptors, the peroxisome proliferator-activated receptors (PPARs). We report that THP-1 monocytes express predominantly PPAR gamma isoform and lower levels of PPAR alpha and PPAR delta isoforms. PPAR mRNA levels are not affected by differentiation of the cells into a macrophage phenotype, nor are they altered following exposure to the classical immune stimulus, lipopolysaccharide. Previous studies have found that PPAR gamma agonists act broadly to inhibit inflammatory responses. The present study explored the action of the PPAR alpha isoform and found that PPAR alpha agonists inhibited the A beta-stimulated expression of TNFalpha and IL-6 reporter genes in a dose-dependent manner. Moreover, the PPAR alpha agonist WY14643 inhibited macrophage differentiation and COX-2 gene expression. However, the PPAR alpha agonists failed to inhibit A beta-stimulated elaboration of neurotoxic factors by THP-1 cells. These findings demonstrate that PPAR alpha acts to suppress a diverse array of inflammatory responses in monocytes.
Combs
C K
CK
Alzheimer Research Laboratory E504, Department of Neurosciences, Case Western Reserve University, School of Medicine, 10900 Euclid Avenue, Cleveland, OH 44106, USA.
Bates
P
P
Karlo
J C
JC
Landreth
G E
GE
D000682:Amyloid / Q000494:pharmacology; D016229:Amyloid beta-Peptides / Q000502:physiology*; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D051546:Cyclooxygenase 2; D006801:Humans; D007249:Inflammation / Q000209:etiology*; D007527:Isoenzymes / Q000378:metabolism; D008264:Macrophages / Q000166:cytology; D008565:Membrane Proteins; D017628:Microglia / Q000502:physiology; D009000:Monocytes / Q000166:cytology / Q000502:physiology; D009498:Neurotoxins / Q000037:antagonists & inhibitors; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000502:physiology; D000067759:Receptor for Advanced Glycation End Products; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000378:metabolism / Q000502:physiology*; D011971:Receptors, Immunologic / Q000502:physiology; D018110:Receptors, Lipoprotein; D051116:Receptors, Scavenger; D051122:Scavenger Receptors, Class B; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D014157:Transcription Factors / Q000819:agonists / Q000378:metabolism / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors; D000093242:Interleukin-6 Inhibitors
D000682:Amyloid; D016229:Amyloid beta-Peptides; D051546:Cyclooxygenase 2; D007527:Isoenzymes; D008565:Membrane Proteins; D009498:Neurotoxins; D011451:Prostaglandin-Endoperoxide Synthases; D011505:Protein-Tyrosine Kinases; D000067759:Receptor for Advanced Glycation End Products; D018160:Receptors, Cytoplasmic and Nuclear; D011971:Receptors, Immunologic; D018110:Receptors, Lipoprotein; D051116:Receptors, Scavenger; D051122:Scavenger Receptors, Class B; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D000093242:Interleukin-6 Inhibitors; C454739:Scarb1 protein, mouse; C496540:PTGS2 protein, human