title: c-Jun and c-Fos regulate the complement factor H promoter in murine astrocytes.
abstract: The complement system is a critical component of innate immunity that requires regulation to avoid inappropriate activation. This regulation is provided by many proteins, including complement factor H (CFH), a critical regulator of the alternative pathway of complement activation. Given its regulatory function, mutations in CFH have been implicated in diseases such as age-related macular degeneration and membranoproliferative glomerulonephritis, and central nervous system diseases such as Alzheimer's disease, Parkinson's disease, and a demyelinating murine model, experimental autoimmune encephalomyelitis (EAE). There have been few investigations on the transcriptional regulation of CFH in the brain and CNS. Our studies show that CFH mRNA is present in several CNS cell types. The murine CFH (mCFH) promoter was cloned and examined through truncation constructs and we show that specific regions throughout the promoter contain enhancers and repressors that are positively regulated by inflammatory cytokines in astrocytes. Database mining of these regions indicated transcription factor binding sites conserved between different species, which led to the investigation of specific transcription factor binding interactions in a 241 base pair (bp) region at -416 bp to -175 bp that showed the strongest activity. Through supershift analysis, it was determined that c-Jun and c-Fos interact with the CFH promoter in astrocytes in this region. These results suggest a relationship between cell cycle and complement regulation, and how these transcription factors and CFH affect disease will be a valuable area of investigation.
authors.affiliation: Interdisciplinary Program in Immunology, University of Iowa, Iowa City, IA 52242, United States.
authors.forename: Laura A
authors.initials: LA
authors.lastname: Fraczek
authors.forename: Carol B
authors.initials: CB
authors.lastname: Martin
authors.forename: Brian K
authors.initials: BK
authors.lastname: Martin
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000276:immunology / Q000378:metabolism*; D001483:Base Sequence; D015153:Blotting, Western; D002453:Cell Cycle; D002460:Cell Line; D003167:Complement Activation / Q000235:genetics* / Q000276:immunology; D017242:Complement Factor H / Q000235:genetics* / Q000276:immunology; D018983:DNA Footprinting; D024202:Electrophoretic Mobility Shift Assay; D005786:Gene Expression Regulation / Q000235:genetics* / Q000276:immunology; D051379:Mice; D008969:Molecular Sequence Data; D010802:Phylogeny; D011401:Promoter Regions, Genetic / Q000235:genetics / Q000276:immunology; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics* / Q000276:immunology; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics* / Q000276:immunology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection
chemical_list: D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D017242:Complement Factor H