Cyclic AMP inhibition of tumor necrosis factor alpha production induced by amyloidogenic C-terminal peptide of Alzheimer's amyloid precursor protein in macrophages: involvement of multiple intracellular pathways and cyclic AMP response element binding protein.
In the present study, we focused on the molecular events involved in tumor necrosis factor-alpha (TNF-alpha) production in response to the amyloidogenic 105-amino acid carboxyl-terminal fragment (CT105) of amyloid precursor protein, a candidate alternative toxic element in Alzheimer's disease pathology, and the mechanisms by which cyclic AMP regulates the relating inflammatory signal cascades. CT105 at nanomolar concentrations strongly activated multiple signaling pathways involving tyrosine kinase-dependent extracellular signal-regulated kinase and p38 mitogen-activated protein kinases. Moreover, phosphatidylinositol 3-kinase/Akt signal was required for excess TNF-alpha production in human macrophages derived from THP-1 cells. Interferon-gamma significantly potentiated the induction of the CT105-mediated signal cascade. These multiple signaling pathways in turn converged, at least in part, at the nuclear transcription factor known as cAMP response element binding protein (CREB), which acts on the TNF-alpha gene promoter through the cAMP response element. The cell-permeable cAMP analog dibutyryl cAMP partially and almost simultaneously suppressed all of these CT105-induced signaling pathways through excessive CREB phosphorylation, which led to decreased CREB DNA binding activity and reduced TNF-alpha expression. Furthermore, dibutyryl cAMP decreased the interaction of the p65 nuclear factor-kappa B with CREB binding protein, thus further inhibiting CT105-mediated TNF-alpha expression. Collectively, the detailed molecular mechanisms of amyloidogenic CT-induced TNF-alpha production as negatively regulated by cAMP may advance the possibility of targeted treatment in Alzheimer's disease.
Chong
Young Hae
YH
Department of Microbiology, College of Medicine, Division of Molecular Biology and Neuroscience, Medical Research Center, Ewha Womans University, Seoul, Korea. younghae@mm.ewha.ac.kr
Shin
Yoo Jung
YJ
Suh
Yoo-Hun
YH
D000544:Alzheimer Disease / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000494:pharmacology*; D002135:Calcium-Binding Proteins; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000494:pharmacology*; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D004247:DNA / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008262:Macrophage Activation; D008264:Macrophages / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D008562:Membrane Glycoproteins; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009419:Nerve Tissue Proteins; D010446:Peptide Fragments / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D015398:Signal Transduction / Q000187:drug effects; D050863:Synaptotagmin I; D050857:Synaptotagmins; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
D016564:Amyloid beta-Protein Precursor; D002135:Calcium-Binding Proteins; D000242:Cyclic AMP; D017362:Cyclic AMP Response Element-Binding Protein; D004247:DNA; D008562:Membrane Glycoproteins; D020928:Mitogen-Activated Protein Kinases; D009419:Nerve Tissue Proteins; D010446:Peptide Fragments; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D050863:Synaptotagmin I; D050857:Synaptotagmins; D014409:Tumor Necrosis Factor-alpha; C494918:AKT1 protein, human