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B and Cyclic Adenosine 5'-Monophosphate Response Element-Binding Protein in Rheumatoid Arthritis Synovial Tissue1
*
Department of Rheumatology, St. Vincent’s University Hospital, Dublin, Ireland; and
Department of Molecular and Cell Biology, Baylor College of Medicine, Houston, TX 77030
Modulation of the NURR subfamily of nuclear receptors may be an
important mechanism regulating pathways associated with inflammatory
joint disease. We examined the signaling mechanisms through which
inflammatory mediators, produced by rheumatoid arthritis (RA) synovial
tissue, contribute to the regulation of the NURR subfamily. Markedly
enhanced expression of NURR1 is observed in synovial tissue of patients
with RA compared with normal subjects. Modulation by proinflammatory
mediators in primary RA and normal synoviocytes shows that
PGE2, IL-1
, and TNF-
markedly enhance NURR1 mRNA and
protein levels in contrast to other subfamily members, NUR77 and NOR-1.
We have established that transcriptional activation of the
NURR1 gene by IL-1 and TNF- requires a
proximal promoter region that contains a consensus NF-
B DNA-binding
motif. IL-1- and TNF--induced NF-B binding to this site is due
predominantly to p65-p50 heterodimer and p50 homodimer subunit protein
complexes. We further demonstrate a direct CREB-1-dependent regulation
by PGE2 situated at promoter region -171/-163. Moreover,
analyses confirm the presence of CREB-1 and NF-B p50 and p65 subunit
binding to the NURR1 promoter under basal conditions in freshly
explanted RA synovial tissue. In summary, enhanced NF-B- and
CREB-1-binding activity on the NURR1 promoter by inflammatory mediators
delineates novel mechanisms in the regulation of NURR1 transcription.
PGE2-, TNF--, and IL-1-dependent stimulation of the
NURR1 gene implies that NURR1 induction represents a point of
convergence of at least two distinct signaling pathways, suggesting an
important common role for this transcription factor in mediating
multiple inflammatory signals.
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