TY - JOUR
T1 - Corticotropin-releasing hormone signaling in synovial tissue vascular endothelium is mediated through the cAMP/CREB pathway
AU - McEvoy, Alice N.
AU - Bresnihan, Barry
AU - Fitzgerald, Oliver
AU - Murphy, Evelyn P.
PY - 2002
Y1 - 2002
N2 - Modulation of locally produced corticotropin-releasing hormone (CRH) is a component of the cytokine network in human inflammatory arthritis. CRH signaling, through the CRH-receptor subtype R1α, may play a role in both vascular changes and pathologic mechanisms associated with joint inflammation. Furthermore, the peripheral actions of CRH may be mediated in part through the NURR subfamily of nuclear orphan receptors. The aim of this study was to establish the signaling mechanisms through which CRH receptor-mediated responses contribute to gene regulation in inflamed synovial vasculature. Immunohistochemical analysis of serial rheumatoid arthritis (RA) tissue sections demonstrates CRH and NURR1 expression in the synovial lining layer, subsynovial lining layer, and the vascular endothelium. The identical pattern of immunolocalization confirms that NURR1 is produced at the same synovial sites shown to produce CRH. The distribution of specific NURR1 staining on the synovial vasculature parallels that observed for CRHR1 expression. Using primary synovial tissue endothelial cells, we demonstrate that CRH induces specific CREB-1 and ATF-2 binding to the NURR1 promoter. We further provide evidence that CRH signaling can be mimicked by activation of cAMP/PKA/CREB using forskolin in primary human microvascular endothelial cells. These data indicate that the CRH receptor-dependent inflammatory response in synovial tissue endothelium is mediated through the cAMP/CREB signaling pathway.
AB - Modulation of locally produced corticotropin-releasing hormone (CRH) is a component of the cytokine network in human inflammatory arthritis. CRH signaling, through the CRH-receptor subtype R1α, may play a role in both vascular changes and pathologic mechanisms associated with joint inflammation. Furthermore, the peripheral actions of CRH may be mediated in part through the NURR subfamily of nuclear orphan receptors. The aim of this study was to establish the signaling mechanisms through which CRH receptor-mediated responses contribute to gene regulation in inflamed synovial vasculature. Immunohistochemical analysis of serial rheumatoid arthritis (RA) tissue sections demonstrates CRH and NURR1 expression in the synovial lining layer, subsynovial lining layer, and the vascular endothelium. The identical pattern of immunolocalization confirms that NURR1 is produced at the same synovial sites shown to produce CRH. The distribution of specific NURR1 staining on the synovial vasculature parallels that observed for CRHR1 expression. Using primary synovial tissue endothelial cells, we demonstrate that CRH induces specific CREB-1 and ATF-2 binding to the NURR1 promoter. We further provide evidence that CRH signaling can be mimicked by activation of cAMP/PKA/CREB using forskolin in primary human microvascular endothelial cells. These data indicate that the CRH receptor-dependent inflammatory response in synovial tissue endothelium is mediated through the cAMP/CREB signaling pathway.
KW - CRH
KW - G protein-coupled receptors
KW - Inflammation
KW - Rheumatoid arthritis
KW - Signaling pathways
KW - Transcription factors
KW - Vascular endothelium
UR - http://www.scopus.com/inward/record.url?scp=0036305914&partnerID=8YFLogxK
U2 - 10.1111/j.1749-6632.2002.tb04209.x
DO - 10.1111/j.1749-6632.2002.tb04209.x
M3 - Article
C2 - 12114266
AN - SCOPUS:0036305914
SN - 0077-8923
VL - 966
SP - 119
EP - 130
JO - Annals of the New York Academy of Sciences
JF - Annals of the New York Academy of Sciences
ER -