Regulation of complement component C3 in astrocytes by IL-1beta and morphine.
Substances of abuse, such as opiates, and astroglial-derived proinflammatory cytokines, such as interleukin (IL)-1beta, likely contribute to the neuroinflammatory and neurodegenerative processes observed in NeuroAIDS in injection drug users. Furthermore, uncontrolled synthesis and activation of complement component C3 in the brain can also lead to inflammation and neurodegeneration. We hypothesized that morphine may alter regulation of the C3 gene by IL-1beta in astrocytes. Our studies demonstrate that IL-1beta induces C3 promoter activity in a CAAT/enhancer-binding protein (C/EBP)-dependent manner. Inhibition of IL-1beta mediated C3 promoter activation by the dominant negative mutant of p38-alpha mitogen-activated protein kinase suggests that IL-1beta induces C3 expression through the activation of C/EBP. Morphine (0.01 microM) in combination with IL-1beta further induced C3 promoter activity. Similarly, the C/EBP-beta isoform liver activating protein and C/EBP-delta-induced C3 promoter activity were upregulated by morphine and IL-1beta. Taken together, this study illustrates that morphine modulates IL-1beta-mediated C3 expression in astrocytic cells.
Maranto
Jeffrey
J
Department of Neuroscience, Temple University School of Medicine, 1900 N. 12th Street, Philadelphia, PA, USA.
Rappaport
Jay
J
Datta
Prasun K
PK
D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism*; D001483:Base Sequence; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism; D002460:Cell Line; D003176:Complement C3 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D024202:Electrophoretic Mobility Shift Assay; D015870:Gene Expression; D005786:Gene Expression Regulation; D006801:Humans; D053583:Interleukin-1beta / Q000378:metabolism*; D008969:Molecular Sequence Data; D009020:Morphine / Q000494:pharmacology*; D009294:Narcotics / Q000494:pharmacology*; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000235:genetics; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D014158:Transcription, Genetic; D014162:Transfection; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D022762:CCAAT-Enhancer-Binding Proteins; D003176:Complement C3; D053583:Interleukin-1beta; D009294:Narcotics; D011994:Recombinant Proteins; D009020:Morphine; D048051:p38 Mitogen-Activated Protein Kinases