Nuclear receptors (NRs) act as ligand‐inducible transcription factors which regulate the expression of target genes upon binding to cognate response elements. The ligand‐dependent activity of the NR activation function AF‐2 is believed to be mediated to the transcription machinery through transcriptional mediators/intermediary factors (TIFs). We report here the cloning of the 160 kDa human nuclear protein TIF2, which exhibits all properties expected for a mediator of AF‐2: (i) it interacts in vivo with NRs in an agonist‐dependent manner; (ii) it binds directly to the ligand‐binding domains (LBDs) of NRs in an agonist‐ and AF‐2‐integrity‐dependent manner in vitro; (iii) it harbours an autonomous transcriptional activation function; (iv) it relieves nuclear receptor autosquelching; and (v) it enhances the activity of some nuclear receptor AF‐2s when overexpressed in mammalian cells. TIF2 exhibits partial sequence homology with the recently isolated steroid receptor coactivator SRC‐1, indicating the existence of a novel gene family of nuclear receptor transcriptional mediators.

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Activation function 2 in the ligand binding domain of nuclear receptors forms a hydrophobic cleft that binds the LXXLL motif of p160 transcriptional coactivators. Here we provide evidence that activation function 2 in the androgen receptor serves as the contact site for the androgen dependent NH 2 -and carboxyl-terminal interaction of the androgen receptor and only weakly interacts with p160 coactivators in an LXXLL-dependent manner. Mutagenesis studies indicate that it is the NH 2 -/ carboxyl-terminal interaction that is required by activation function 2 to stabilize helix 12 and slow androgen dissociation critical for androgen receptor activity in vivo. The androgen receptor recruits p160 coactivators through its NH 2 -terminal and DNA binding domains in an LXXLL motif-independent manner. The results suggest a novel function for activation function 2 and a unique mechanism of nuclear receptor transactivation.Steroid receptors interact with coactivators during the recruitment of active transcription initiation complexes required for hormone-regulated gene transcription (1). Transcriptional activation domains in the steroid receptors that may mediate these interactions include activation function 1 in the NH 2 -terminal domain and activation function 2 (AF2) 1 in the ligand binding domain (LBD). Recent studies have focused on a family of p160 coactivators that interact with the AF2 region that include steroid receptor coactivator 1 (SRC1) (2) and the human transcriptional intermediary factor 2 (TIF2) (3). SRC1 and TIF2 contain distinct nuclear receptor interaction domains in the central and/or carboxyl-terminal regions (3, 4). Mutagenesis studies demonstrated a functional link between AF2 activity in the LBD and the binding of p160 coactivators (5, 6). The p160 coactivators interact with the AF2 hydrophobic surface of the LBD through conserved LXXLL motifs that form amphipathic ␣ helices (7, 8). Recent co-crystal structures of nuclear receptor LBDs and LXXLL motif fragments confirm that AF2 recruits TIF2 and SRC1 through their LXXLL motifs (6, 9 -11). A multistep mechanism for transcriptional activation by nuclear receptors involves hormone-dependent recruitment and association through these LXXLL binding motifs of histone acetyltransferase activity associated with the p160 coactivator family, CREB-binding protein/p300, and p300/CREB-binding protein-associated factor, resulting in chromatin remodeling (12, 13) and the formation of a transcriptionally competent Srb/mediator coactivator complex (thyroid hormone receptorassociated protein/vitamin D receptor-interacting protein) complex (14). However, androgen receptor (AR) AF2 activity is not detected in a variety of mammalian cell lines (15-18) despite homology of the region with other nuclear receptors. We therefore investigated the mechanism whereby AR recruits p160 coactivators and the role of AF2 in AR function. It is demonstrated that weak interactions between the AR LBD and SRC1 and TIF2 correspond with weak AR AF2 activity. The AF2 surface in the AR LBD ins...

Rosacea is a common skin disease with a high impact on quality of life. Characterized by erythema, edema, burning pain, immune infiltration, and facial skin fibrosis, rosacea has all the characteristics of neurogenic inflammation, a condition induced by sensory nerves via antidromically released neuromediators. To investigate the hypothesis of a central role of neural interactions in the pathophysiology, we analyzed molecular and morphological characteristics in the different subtypes of rosacea by immunohistochemistry, double immunofluorescence, morphometry, real-time PCR, and gene array analysis, and compared the findings with those for lupus erythematosus or healthy skin. Our results showed significantly dilated blood and lymphatic vessels. Signs of angiogenesis were only evident in phymatous rosacea. The number of mast cells and fibroblasts was increased in rosacea, already in subtypes in which fibrosis is not clinically apparent, indicating early activation. Sensory nerves were closely associated with blood vessels and mast cells, and were increased in erythematous rosacea. Gene array studies and qRT-PCR confirmed upregulation of genes involved in vasoregulation and neurogenic inflammation. Thus, dysregulation of mediators and receptors implicated in neurovascular and neuroimmune communication may be crucial at early stages of rosacea. Drugs that function on neurovascular and/or neuroimmune communication may be beneficial for the treatment of rosacea.

Rosacea is a chronic inflammatory skin disease of unknown etiology. Although described centuries ago, the pathophysiology of this disease is still poorly understood. Epidemiological studies indicate a genetic component, but a rosacea gene has not been identified yet. Four subtypes and several variants of rosacea have been described. It is still unclear whether these subtypes represent a “developmental march” of different stages or are merely part of a syndrome that develops independently but overlaps clinically. Clinical and histopathological characteristics of rosacea make it a fascinating “human disease model” for learning about the connection between the cutaneous vascular, nervous, and immune systems. Innate immune mechanisms and dysregulation of the neurovascular system are involved in rosacea initiation and perpetuation, although the complex network of primary induction and secondary reaction of neuroimmune communication is still unclear. Later, rosacea may result in fibrotic facial changes, suggesting a strong connection between chronic inflammatory processes and skin fibrosis development. This review highlights recent molecular (gene array) and cellular findings and aims to integrate the different body defense mechanisms into a modern concept of rosacea pathophysiology.

Rosacea is a common chronic inflammatory skin disease of unknown etiology. Our knowledge about an involvement of the adaptive immune system is very limited. We performed detailed transcriptome analysis, quantitative real-time reverse-transcriptase-PCR, and quantitative immunohistochemistry on facial biopsies of rosacea patients, classified according to their clinical subtype. As controls, we used samples from patients with facial lupus erythematosus and healthy controls. Our study shows significant activation of the immune system in all subtypes of rosacea, characterizing erythematotelangiectatic rosacea (ETR) already as a disease with significant influx of proinflammatory cells. The T-cell response is dominated by Th1/Th17-polarized immune cells, as demonstrated by significant upregulation of IFN-γ or IL-17, for example. Chemokine expression patterns support a Th1/Th17 polarization profile of the T-cell response. Macrophages and mast cells are increased in all three subtypes of rosacea, whereas neutrophils reach a maximum in papulopustular rosacea. Our studies also provide evidence for the activation of plasma cells with significant antibody production already in ETR, followed by a crescendo pattern toward phymatous rosacea. In sum, Th1/Th17 polarized inflammation and macrophage infiltration are an underestimated hallmark in all subtypes of rosacea. Therapies directly targeting the Th1/Th17 pathway are promising candidates in the future treatment of this skin disease.

We quantified incidence rates and characteristics of patients with rosacea diagnosed in clinical practice in a large epidemiological study using primary care data from the U.K. Smoking was associated with a substantially reduced risk of developing rosacea.

Rosacea is a frequent chronic inflammatory skin disease of unknown etiology. Because early rosacea reveals all characteristics of neurogenic inflammation, a central role of sensory nerves in its pathophysiology has been discussed. Neuroinflammatory mediators and their receptors involved in rosacea are poorly defined. Good candidates may be transient receptor potential (TRP) ion channels of vanilloid type (TRPV), which can be activated by many trigger factors of rosacea. Interestingly, TRPV2, TRPV3, and TRPV4 are expressed by both neuronal and non-neuronal cells. Here, we analyzed the expression and distribution of TRPV receptors in the various subtypes of rosacea on non-neuronal cells using immunohistochemistry, morphometry, double immunoflourescence, and quantitative real-time PCR (qRT-PCR) as compared with healthy skin and lupus erythematosus. Our results show that dermal immunolabeling of TRPV2 and TRPV3 and gene expression of TRPV1 is significantly increased in erythematotelangiectatic rosacea (ETR). Papulopustular rosacea (PPR) displayed an enhanced immunoreactivity for TRPV2, TRPV4, and also of TRPV2 gene expression. In phymatous rosacea (PhR)-affected skin, dermal immunostaining of TRPV3 and TRPV4 and gene expression of TRPV1 and TRPV3 was enhanced, whereas epidermal TRPV2 staining was decreased. Thus, dysregulation of TRPV channels also expressed by non-neuronal cells may be critically involved in the initiation and/or development of rosacea. TRP ion channels may be targets for the treatment of rosacea.