The interplay between cyclic AMP, MAPK, and NF-κB pathways in response to proinflammatory signals in microglia.
Cyclic AMP is an important intracellular regulator of microglial cell homeostasis and its negative perturbation through proinflammatory signaling results in microglial cell activation. Though cytokines, TNF-α and IL-1β, decrease intracellular cyclic AMP, the mechanism by which this occurs is poorly understood. The current study examined which signaling pathways are responsible for decreasing cyclic AMP in microglia following TNF-α stimulation and sought to identify the role cyclic AMP plays in regulating these pathways. In EOC2 microglia, TNF-α produced a dramatic reduction in cyclic AMP and increased cyclic AMP-dependent PDE activity that could be antagonized by Rolipram, myristoylated-PKI, PD98059, or JSH-23, implicating a role for PDE4, PKA, MEK, and NF-κB in this regulation. Following TNF-α there were significant increases in iNOS and COX-2 immunoreactivity, phosphorylated ERK1/2 and NF-κB-p65, IκB degradation, and NF-κB p65 nuclear translocation, which were reduced in the presence of high levels of cyclic AMP, indicating that reductions in cyclic AMP during cytokine stimulation are important for removing its inhibitory action on NF-κB activation and subsequent proinflammatory gene expression. Further elucidation of the signaling crosstalk involved in decreasing cyclic AMP in response to inflammatory signals may provide novel therapeutic targets for modulating microglial cell activation during neurological injury and disease.
The Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, Miami, FL 33136, USA ; Department of Neurological Surgery, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
Mousumi
M
Ghosh
The Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
Vladimir
V
Aguirre
The Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
Khine
K
Wai
The Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
Hady
H
Felfly
The Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, Miami, FL 33136, USA ; Department of Neurological Surgery, University of Miami Miller School of Medicine, Miami, FL 33136, USA ; Department of Neurology, University of Miami Miller School of Medicine, Miami, FL 33136, USA ; Department of Cell Biology, University of Miami Miller School of Medicine, Miami, FL 33136, USA ; The Neuroscience Program, University of Miami Miller School of Medicine, Miami, FL 33136, USA ; The Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
W Dalton
WD
Dietrich
The Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, Miami, FL 33136, USA ; Department of Neurological Surgery, University of Miami Miller School of Medicine, Miami, FL 33136, USA ; The Neuroscience Program, University of Miami Miller School of Medicine, Miami, FL 33136, USA ; The Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
Damien D
DD
Pearse
D002460:Cell Line; D000242:Cyclic AMP / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D018836:Inflammation Mediators / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D017628:Microglia / Q000378:metabolism / Q000473:pathology; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D018836:Inflammation Mediators; D053583:Interleukin-1beta; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D000242:Cyclic AMP; D020929:Mitogen-Activated Protein Kinase Kinases