Duration of alpha 1-antichymotrypsin gene activation by interleukin-1 is determined by efficiency of inhibitor of nuclear factor kappa B alpha resynthesis in primary human astrocytes.
Expression of alpha1antichymotrypsin (ACT) is significantly activated by interleukin-1 (IL-1) in human astrocytes; however, it is barely affected by IL-1 in hepatocytes. This tissue-specific regulation depends upon an enhancer that contains both nuclear factor kappaB (NF-kappaB) and activating protein 1 (AP-1) elements, and is also observed for an NF-kappaB reporter but not for an AP-1 reporter. We found efficient activation of NF-kappaB binding in both cell types; however, this binding was persistent in glial cells and only transient in hepatocytes. IL-1-activated NF-kappaB complexes consisted of p65 and p50, with p65 transiently phosphorylated on serine 536 in glial cells whereas more persistently in hepatic cells. Overexpression of p65 or constitutively active IKKbeta (inhibitor of NF-kappaB kinase beta) resulted in an efficient activation of the ACT reporter in hepatic cells, indicating that a specific mechanism exists in these cells terminating IL-1 signaling. IL-1 effectively induced the degradation of inhibitor of NF-kappaBalpha (IkBalpha) and IkBepsilon in both cell types but IkBbeta was not affected. However, IkBalpha was resynthesized much more rapidly in hepatic cells in comparison to glial cells. In addition, the initial levels of IkBalpha were much lower in glial cells. We propose that the tissue-specific regulation of the ACT gene expression by IL-1 is determined by different efficiencies of IkBalpha resynthesis in glial and hepatic cells.
Kiss
Daniel L
DL
Department of Biological, Geological and Environmental Sciences, Cleveland State University, Cleveland, Ohio, USA.
Xu
Weili
W
Gopalan
Sunita
S
Buzanowska
Katarzyna
K
Wilczynska
Katarzyna M
KM
Rydel
Russell E
RE
Kordula
Tomasz
T
D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D006801:Humans; D020672:I-kappa B Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D007375:Interleukin-1 / Q000494:pharmacology*; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000096:biosynthesis* / Q000235:genetics; D015533:Transcriptional Activation; D000514:alpha 1-Antichymotrypsin / Q000235:genetics* / Q000378:metabolism*
D020672:I-kappa B Proteins; D007375:Interleukin-1; D016328:NF-kappa B; D000514:alpha 1-Antichymotrypsin