A novel role of interleukin-1-converting enzyme in cytokine-mediated inducible nitric oxide synthase gene expression: Implications for neuroinflammatory diseases.
Inducible nitric oxide synthase (iNOS)-derived NO plays an important role in several neurological disorders. Understanding of mechanisms involved in the regulation of iNOS induction is of particular interest. Here, we investigated mechanisms of iNOS induction in rat astrocytes (AC) and in brain endothelial cells (BEC). We find that activation of AC or BEC with pro-inflammatory cytokines reveals a different cell-specific activation pattern for iNOS expression. Despite these differences, in both cell types iNOS expression and activity exclusively depends on the endogenous availability of bioactive IL-1beta as inhibition of ICE activity significantly decreases iNOS promoter activity, iNOS expression and enzyme activity. In summary, we here provide evidence that ICE represents a target for modulating iNOS expression and high-output NO formation in AC and BEC, to our knowledge the first report of a role of ICE in iNOS expression and the advantage of ICE inhibition in attenuating NO mediated inflammation and pathology.
Jüttler
Eric
E
Department of Neurology, Ruprechts-Karls-University, Im Neuenheimer Feld 400, D-69120 Heidelberg, Germany.
Bonmann
Eckhard
E
Spranger
Matthias
M
Kolb-Bachofen
Victoria
V
Suschek
Christoph V
CV
D000818:Animals; D001253:Astrocytes / Q000378:metabolism*; D001921:Brain / Q000166:cytology / Q000378:metabolism; D020170:Caspase 1 / Q000378:metabolism*; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism*; D042783:Endothelial Cells / Q000378:metabolism*; D004790:Enzyme Induction / Q000502:physiology; D015870:Gene Expression; D005786:Gene Expression Regulation; D006801:Humans; D007150:Immunohistochemistry; D007249:Inflammation; D007371:Interferon-gamma / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D011994:Recombinant Proteins / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D016207:Cytokines; D053583:Interleukin-1beta; D012333:RNA, Messenger; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D052247:Nitric Oxide Synthase Type II; D020170:Caspase 1