TY - JOUR
T1 - Increased expression of the orphan nuclear receptor NURR1 in psoriasis and modulation following TNF-α inhibition
AU - O'Kane, Marina
AU - Markham, Trevor
AU - McEvoy, Alice N.
AU - Fearon, Ursula
AU - Veale, Doug J.
AU - Fitzgerald, Oliver
AU - Kirby, Brian
AU - Murphy, Evelyn P.
PY - 2008/2
Y1 - 2008/2
N2 - The orphan nuclear receptor NURR1 belongs to the NR4A subfamily of transcription factors which are emerging as important mediators of cytokine and growth factor signaling. The transcriptional function of these ligand-independent and constitutively active receptors is controlled at the level of expression and nuclear localization. This study examines the expression of NURR1 in psoriasis and biological effects on this receptor following inhibition of tumor necrosis factor-α (TNF-α) signaling. We report increased expression of NURR1 mRNA and protein in involved psoriasis skin compared with uninvolved and normal skin, which correlates significantly (P=0.0055) with clinical measures of the psoriasis area and severity index. Enhanced NURR1 expression localizes to both nucleus and cytoplasm of cells of involved epidermis, blood vessels, and inflammatory infiltrates, in contrast to predominant cytoplasmic distribution in uninvolved and normal skin. Endogenous NURR1 levels are rapidly and selectively increased in response to proinflammatory agonists and growth factors in normal dermal endothelial cells. Following TNF-α inhibition with infliximab or etanercept, NURR1 mRNA and protein levels in involved skin are significantly decreased and cytoplasmic distribution is restored. These findings establish the aberrant expression and distribution of NURR1 in psoriasis and suggest that clinical benefits of TNF-α inhibition may be mediated through altered NURR1 activity.
AB - The orphan nuclear receptor NURR1 belongs to the NR4A subfamily of transcription factors which are emerging as important mediators of cytokine and growth factor signaling. The transcriptional function of these ligand-independent and constitutively active receptors is controlled at the level of expression and nuclear localization. This study examines the expression of NURR1 in psoriasis and biological effects on this receptor following inhibition of tumor necrosis factor-α (TNF-α) signaling. We report increased expression of NURR1 mRNA and protein in involved psoriasis skin compared with uninvolved and normal skin, which correlates significantly (P=0.0055) with clinical measures of the psoriasis area and severity index. Enhanced NURR1 expression localizes to both nucleus and cytoplasm of cells of involved epidermis, blood vessels, and inflammatory infiltrates, in contrast to predominant cytoplasmic distribution in uninvolved and normal skin. Endogenous NURR1 levels are rapidly and selectively increased in response to proinflammatory agonists and growth factors in normal dermal endothelial cells. Following TNF-α inhibition with infliximab or etanercept, NURR1 mRNA and protein levels in involved skin are significantly decreased and cytoplasmic distribution is restored. These findings establish the aberrant expression and distribution of NURR1 in psoriasis and suggest that clinical benefits of TNF-α inhibition may be mediated through altered NURR1 activity.
UR - http://www.scopus.com/inward/record.url?scp=38149108222&partnerID=8YFLogxK
U2 - 10.1038/sj.jid.5701023
DO - 10.1038/sj.jid.5701023
M3 - Article
C2 - 17671512
AN - SCOPUS:38149108222
SN - 0022-202X
VL - 128
SP - 300
EP - 310
JO - Journal of Investigative Dermatology
JF - Journal of Investigative Dermatology
IS - 2
ER -