Increased Expression of the Orphan Nuclear Receptor NURR1 in Psoriasis and Modulation following TNF-α Inhibition

Abstract

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.

Effect of infliximab on the levels of TNF-alpha and TGF-beta in the whole blood cultures of irradiated patients.

“…We took advantage of the fact that TNF-α is one of the factors effecting TGF-β levels by inducing TGF-β expression [13,14], and so we assumed that lower TNF-α level would result in lower TGF-β expression. There are very little reports [24,25] in the literature available about radio-protective role of Infliximab and none referring directly to radio-protective role of Infliximab in irradiated patients. Post-radiation fibrosis is a serious clinical complication influencing the quality of life of irradiated patients, leading to the deterioration of their circulatory and respiratory efficiency and even to death, depending on the extent of the fibrotic changes.…”

Limited Role of Nuclear Receptor Nur77 in Escherichia coli-Induced Peritonitis

“…This nuclear receptor plays a role in chronic inflammation conditions such as atherosclerosis (10,16,17) and rheumatoid arthritis (32). Nurr1, another member of the NR4A subfamily, has also been implicated in several chronic inflammatory diseases, namely, psoriasis (33), inflammatory arthritis (34), and osteoarthritis (35). Furthermore, all three NR4A subfamily members have been implicated in atopic dermatitis (36).…”

The NR4A receptors Nurr1 and Nur77 are increased in human placenta from women with gestational diabetes

“…Consistent with these findings, NR4A receptors regulate a number of key cellular functions, including inflammation, proliferation, adhesion, metabolism and cell survival [1,4,5,8e12]. As such, they have been implicated in a number of diseases including atherosclerosis [5,9], diabetes [10,13], arthritis [6,14,15] and cancer [16].…”