The source of complement, a major contributor to the pathology of diseases such as multiple sclerosis (MS) and experimental allergic encephalomyelitis (EAE), is unclear. Despite this lack of information, the role of complement in demyelinating disease has been extensively studied. These studies have shown 1) the presence of the terminal components of complement which form the lytic membrane attack complex, 2) activation of complement by myelin and myelin basic protein and 3) the destructive effects of complement activation specifically inflammation, demyelination and tissue destruction. Our preliminary data demonstrate that astrogliomas and primary rat astrocytes synthesize several components of the complement system and that synthesis can be markedly upregulated by the cytokine, interferon-gamma (IFN-gamma). The regulation of complement synthesis by IFN-gamma is of particular interest as all other cell types known to synthesize complement are refractory to the effect of this cytokine. We hypothesize that local complement production, enhanced in astrocytes by the effects of cytokines such as IFN-gamma, participates in the pathogenesis of neural autoimmune diseases such as MS or EAE. Because of the potential for complement-mediated tissue destruction and inflammation in neural autoimmune diseases, we feel it is important to more fully understand the production and regulation of complement by astrocytes. We will focus on components involved in the activation of the alternative pathway of complement (C3, factors B and D) as all of these components are synthesized by astroglioma cells and rat primary astrocytes, and on one of the regulatory molecules in the complement system, decay accelerating factor. We will characterize the biosynthesis and functionality of these components as produced by the astroglioma cell line D54-MG, which we have found to be a representative cell type with respect to synthesis of complement. We will also examine the induction of complement genes by IFN- gamma by the analysis of transcription rates, steady-state mRNA levels, mRNA stability and protein expression. Further, we will delineate the tissue-specific cis and trans-acting transcriptional control structures involved in regulation of C3 gene expression in astrogliomas and rat primary astrocytes. The studies proposed in this application will contribute to understanding the role played by complement in the central nervous system. In addition, this information will form the basis for comparing the production and regulation of other complement by these cell types, as well as in specific neural disease states such as MS and EAE.

Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Alabama Birmingham
United States
Zip Code
Broeke, Robert Ten; Leusink-Muis, Thea; Hilberdink, Rogier et al. (2004) Specific modulation of calmodulin activity induces a dramatic production of superoxide by alveolar macrophages. Lab Invest 84:29-40
Choi, Chulhee; Jeong, Eunjoo; Benveniste, Etty N (2004) Caspase-1 mediates Fas-induced apoptosis and is up-regulated by interferon-gamma in human astrocytoma cells. J Neurooncol 67:167-76
Park, Jinseu; Choi, Kyungsun; Jeong, Eunjoo et al. (2004) Reactive oxygen species mediate chloroquine-induced expression of chemokines by human astroglial cells. Glia 47:9-20
Kim, S; Choi, K; Kwon, D et al. (2004) Ubiquitin-proteasome pathway as a primary defender against TRAIL-mediated cell death. Cell Mol Life Sci 61:1075-81
Choi, Chulhee; Benveniste, Etty N (2004) Fas ligand/Fas system in the brain: regulator of immune and apoptotic responses. Brain Res Brain Res Rev 44:65-81
Repovic, Pavle; Mi, Kaihong; Benveniste, Etty N (2003) Oncostatin M enhances the expression of prostaglandin E2 and cyclooxygenase-2 in astrocytes: synergy with interleukin-1beta, tumor necrosis factor-alpha, and bacterial lipopolysaccharide. Glia 42:433-46
Ten Broeke, Robert; Brandhorst, Marcel C; Leusink-Muis, Thea et al. (2003) Ca2+ sensors modulate asthmatic symptoms in an allergic model for asthma. Eur J Pharmacol 476:151-7
Park, Jinseu; Kwon, Daeho; Choi, Chulhee et al. (2003) Chloroquine induces activation of nuclear factor-kappaB and subsequent expression of pro-inflammatory cytokines by human astroglial cells. J Neurochem 84:1266-74
Choi, Kyungsun; Benveniste, Etty N; Choi, Chulhee (2003) Induction of intercellular adhesion molecule-1 by Fas ligation: proinflammatory roles of Fas in human astroglioma cells. Neurosci Lett 352:21-4
Repovic, Pavle; Benveniste, Etty N (2002) Prostaglandin E2 is a novel inducer of oncostatin-M expression in macrophages and microglia. J Neurosci 22:5334-43

Showing the most recent 10 out of 129 publications