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on IL-6-Induced 
2-Macroglobulin Expression Is Due to Activation of NF-
B1
*
Institut für Biochemie, Universitätsklinikum der Rheinisch-Westfälischen Technischen Hochschule Aachen, Aachen, Germany; and
Klinik für Gastroenterologie, Hepatologie und Infektiologie, Medizinische Klinik der Heinrich-Heine Universität, Düsseldorf, Germany
The cross-talk between the signal transduction of simultaneous
acting cytokines largely determines the final impact of cytokines on
their target genes. Both NF-
B and STAT3 are transcription factors
well known to be activated by many stimuli and to mediate
transcriptional activation by binding to specific enhancer sequences.
In this study, it is analyzed how IL-1
inhibits IL-6-induced
transcriptional activation of the 
2-macroglobulin
promoter. It is shown that IL-1 prevents STAT3 binding to the two
STAT3-responsive sites within the 2-macroglobulin
promoter by association of IL-1-activated NF-B to this region.
The observation that inhibition of IL-6-induced transcriptional
activation of this promoter by IL-1 is reversed by cotransfection
with I-B provides evidence that NF-B activation by IL-1 is
responsible for inhibition of IL-6-mediated trans
activation of the 2-macroglobulin gene. Accordingly,
cotransfection of the NF-B subunits p50 or p65 themselves inhibited
activation of the 2-macroglobulin promoter by IL-6.
Introduction of point mutations in each of the two NF-B sites
overlapping the two STAT3 binding sites within the
2-macroglobulin promoter provides evidence that each of
these two sites counteracts transcriptional activation via STAT3. Most
interestingly, at least one functional NF-B consensus site is
essential for the IL-6-induced transcriptional activation of the
2-macroglobulin promoter. Additional data are provided
indicating that the activation of NF-B by IL-1 is also
responsible for the inhibition of other IL-6-inducible genes, such as
the 1-antichymotrypsin gene as well as the suppressor of
cytokine signaling 3 gene, suggesting a more general relevance of this
mechanism for transcriptional regulation.
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