After 16 weeks, adalimumab demonstrated significantly superior efficacy and more rapid improvements in psoriasis compared with either methotrexate or placebo.

Pineal gland hormone melatonin binds and activates an orphan of the nuclear receptor superfamily.Michael Becker-André , Irmgard Wiesenberg, Nicole Schaeren-Wiemers, Elisabeth André , Martin Missbach, Jean-Hilaire Saurat, and Carsten Carlberg Correction submitted by Drs. Becker-André , SchaerenWiemers, and André:The article reported the identification of the pineal gland hormone melatonin as a natural ligand of the nuclear orphan receptor RZR␤. The article described transient transfection assays showing stimulation of RZR␤ transactivation by melatonin and in vitro binding studies showing a direct interaction between RZR␤ and melatonin. We were, however, not able to reproduce any of these experiments nor could we determine the reason for this failure. As the central finding of the article is based on these assays, we do not consider the drawn conclusions valid. All other data in the publication including our studies to localize RZR␤ mRNA using in situ hybridization and quantitative PCR are as published. We apologize to all investigators who have spent time and effort to reproduce parts of the work using the in vitro assays described in the article.Addition submitted by Drs. Wiesenberg, Missbach, Saurat, and Carlberg: RZR␤ belongs to the RZR/ROR family of nuclear receptors (1), where the members of this family have been shown to act as ligand-independent transcription factors that bind to monomeric binding sites mediating a high constitutive transcriptional activity (2-5). Recently, Greiner et al. (6) reported failure in observing transcriptional activity of RZR␤ on monomeric sites and its modulation by melatonin. However, in some cell lines, e.g. Drosophila SL-3 cells, the constitutive activity of RZR␤ and RZR/ROR␣ can clearly be reduced, e.g. by the omission of serum to the cell culture medium (2,7,8). Under these restricted experimental conditions RZR␤ and RZR/ROR␣ reproducibly function as ligand-dependent nuclear receptors (7-10). Ligand binding assays have been performed with cells overexpressing RZR/ROR and in vitro translated RZR/ROR (7, 8), but not with the purified receptor. This suggests but does not prove that melatonin is a ligand of RZR/ROR. However, the first report of a melatonin response element in the promoter of the human 5-lipoxygenase gene (11) has demonstrated an essential role of RZR/ROR as a mediator of nuclear melatonin signaling.

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Ligands of the aryl hydrocarbon receptor (AHR), a transcription factor mediating the effects of dioxin, favor Th17 differentiation and exacerbate autoimmunity in mice. We investigated how AHR ligands affected human T-cell polarization. We found that the high affinity and stable AHR-ligand dioxin as well as the natural AHR-ligand 6-formylinolo [3,2-b] carbazole induced the downstream AHR-target cytochrome P450A1, and without affecting IFN-c, they enhanced IL-22 while simultaneously decreasing IL-17A production by CD4 1 T cells. The specific AHRinhibitor CH-223191 abolished these effects. Furthermore, blockade of IL-23 and IL-1, important for Th17 expansion, profoundly decreased IL-17A but not IL-22 production. AHR agonists reduced the expression of the Th17 master transcription factor retinoic acid-related orphan receptor C (RORC), without affecting T-bet, GATA-3 and Foxp3. They also decreased the expression of the IL-23 receptor. Importantly, AHR-ligation did not only decrease the number of Th17 cells but also primed naïve CD4 1 T cells to produce IL-22 without IL-17 and IFN-c. Furthermore, IL-22 single producers did not express CD161, which distinguished them from the CD161 1 Th17 cells. Hence, our data provide compelling evidence that AHR activation participates in shaping human CD4 1 T-cell polarization favoring the emergence of a distinct subset of IL-22-producing cells that are independent from the Th17 lineage. IntroductionLocal cytokine milieu during antigen presentation profoundly affects the differentiation program of CD4 1 T cells [1]. In the mouse, TGF-b, in the presence of IL-6 and pro-inflammatory cytokines, favors the emergence of Th17 cells that produce IL-17 and express the master transcription factor retinoic acid-related orphan receptor (ROR)gt [2][3][4][5][6]. Th17 cells are expanded and terminally differentiated in the presence of . Human Th17 cells may be generated in the presence of IL-1 and IL-23; IL-1 and IL-6; or . Th17 cells express CCR6 and 2450produce the CCR6-ligand CCL20, thereby amplifying Th17 cell recruitment at sites of inflammation [11]. IL-22, a member of the IL-10-family, is produced by Th17 cells, and to some extent by Th1 cells, NKT cells, NK cells and lymphoid tissue inducer-like cells [12]. IL-22 signals via a receptor consisting of IL-22R and IL-10R2 subunits [11]. Cells of hemapoietic origin do not express IL-22R; instead, IL-2R is highly expressed by epithelial cells of the gastrointestinal tract and the skin. In the mouse, IL-23 was shown to drive preferential expansion of cells that co-express IL-22 and IL-17, that may synergize to augment the expression of genes involved in defense against microbial pathogens [13,14]. However, several mouse models of infection and autoimmunity suggested distinct roles for .In addition to cytokines, other mediators may impact CD4 1 T-cell differentiation. We and others have shown that prostaglandin E2 (PGE2) favors human Th17 expansion [20][21][22]. Furthermore, ligands of the aryl hydrocarbon receptor (AHR) exert a role. AHR is a...

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Several million people are exposed to dioxin and dioxin-like compounds, primarily through food consumption. Skin lesions historically called "chloracne" are the most specific sign of abnormal dioxin exposure and classically used as a key marker in humans. We followed for 5 years a man who had been exposed to the most toxic dioxin, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), at a single oral dose of 5 million-fold more than the accepted daily exposure in the general population. We adopted a molecular medicine approach, aimed at identifying appropriate therapy. Skin lesions, which progressively covered up to 40% of the body surface, were found to be hamartomas, which developed parallel to a complete and sustained involution of sebaceous glands, with concurrent transcriptomic alterations pointing to the inhibition of lipid metabolism and the involvement of bone morphogenetic proteins signaling. Hamartomas created a new compartment that concentrated TCDD up to 10-fold compared with serum and strongly expressed the TCDD-metabolizing enzyme cytochrome P450 1A1, thus representing a potentially significant source of enzymatic activity, which may add to the xenobiotic metabolism potential of the classical organs such as the liver. This historical case provides a unique set of data on the human tissue response to dioxin for the identification of new markers of exposure in human populations. The herein discovered adaptive cutaneous response to TCDD also points to the potential role of the skin in the metabolism of food xenobiotics.