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.

Cannabinoid Receptor 2 Suppresses Leukocyte Inflammatory Migration by Modulating the JNK/c-Jun/Alox5 Pathway

“…As the most highly activated target of JNK, activated c-Jun has been reported to directly trans-activate many key genes involved in the inflammation process (17,52,53). Here we demonstrate that alox5 is a direct target of c-Jun and that it could be transcriptionally up-regulated by phosphorylated c-Jun.…”

“…5, E and F). c-Jun regulates the transcription of genes widely involved in cell migration, wound healing, and inflammation, and its activity is regulated by JNK (52)(53)(54). Decreased c-Jun-targeted gene transcription might be responsible for blocking leukocyte migration by Cnr2 activation.…”

Cadmium Induces Glomerular Endothelial Cell–Specific Expression of Complement Factor H via the −1635 AP-1 Binding Site

“…Our study also found that although Cd activates multiple pathways in HRGECs, only the JNK pathway inhibitor eliminated the Cd-induced increase of CFH gene expression and CFH secretion, suggesting that the JNK/AP-1 pathway plays a key role in regulating the transcription of the CFH gene. In murine astrocytes, Fraczek et al (48) identified a 241-bp region at 2416 bp to 2175 bp on the mouse Cfh gene promoter that showed transcriptional activity with possible binding interactions with c-Jun and c-Fos. In the current study, we did not find AP-1 binding in the corresponding region on human CFH promoter in HRGECs but identified an AP-1 binding site at 21635 of the human CFH promoter, which mediates c-Jun-and c-Fosregulated CFH gene expression.…”

The critical role of adrenomedullin and its binding protein, AMBP-1, in neuroprotection

“…We have recently shown that systemically administered AMBP-1 can enter the brain after ischemic stroke (Chaung et al , 2011 ). Local AMBP-1 expression in the brain has also been shown in cerebral endothelial cells (Vastag et al , 1998 ), neurons (Thomas et al , 2000 ), and astrocytes (Fraczek et al , 2011 ). AMBP-1 regulates the complement cascade by binding to C3b and preventing the formation of the alternative complement pathway C3 convertase, C3bBb (Whaley and Ruddy , 1976 ).…”