Increased expression of the orphan nuclear receptor NURR1 in psoriasis and modulation following TNF-alpha inhibition.
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-alpha (TNF-alpha) 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-alpha 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-alpha inhibition may be mediated through altered NURR1 activity.
O'Kane
Marina
M
College of Life Sciences, UCD Veterinary Sciences Centre, Dublin, Ireland.
Markham
Trevor
T
McEvoy
Alice N
AN
Fearon
Ursula
U
Veale
Doug J
DJ
FitzGerald
Oliver
O
Kirby
Brian
B
Murphy
Evelyn P
EP
D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D002455:Cell Division / Q000502:physiology; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D020405:Dermis / Q000098:blood supply / Q000166:cytology; D042783:Endothelial Cells / Q000473:pathology / Q000502:physiology; D005363:Ficusin / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D000069285:Infliximab; D015603:Keratinocytes / Q000473:pathology* / Q000502:physiology*; D019394:Ki-67 Antigen / Q000378:metabolism; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D017319:Photosensitizing Agents / Q000494:pharmacology; D011565:Psoriasis / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D012333:RNA, Messenger / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014466:Ultraviolet Rays
D000893:Anti-Inflammatory Agents; D000911:Antibodies, Monoclonal; D004268:DNA-Binding Proteins; D019394:Ki-67 Antigen; C539882:NR4A2 protein, human; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D017319:Photosensitizing Agents; D012333:RNA, Messenger; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D000069285:Infliximab; D005363:Ficusin