Human S100A7 (psoriasin) is overexpressed in inflammatory diseases. The recently discovered, co-evolved hS100A15 is almost identical in sequence and up-regulated with hS100A7 during cutaneous inflammation. The functional role of these closely related proteins for inflammation remains undefined. By generating specific Abs, we demonstrate that hS100A7 and hS100A15 proteins are differentially expressed by specific cell types in the skin. Although highly homologous, both proteins are chemoattractants with distinct chemotactic activity for leukocyte subsets. We define RAGE (receptor for advanced glycation end products) as the hS100A7 receptor, whereas hS100A15 functions through a Gi protein-coupled receptor. hS100A7-RAGE binding, signaling, and chemotaxis are zinc-dependent in vitro, reflecting the previously reported zinc-mediated changes in the hS100A7 dimer structure. When combined, hS100A7 and hS100A15 potentiate inflammation in vivo. Thus, proinflammatory synergism in disease may be driven by the diverse biology of these almost identical proteins that have just recently evolved. The identified S100A7 interaction with RAGE may provide a novel therapeutic target for inflammation.

The rat opioid receptor is alternatively spliced into two isoforms (MOR1 and MOR1B) which differ in length and amino acid composition at the carboxyl terminus. ]enkephalin (DAMGO) with similar affinity and exhibit functional coupling to adenylyl cyclase with similar efficiency. However, the shorter isoform, MOR1B, desensitized at a slower rate during prolonged DAMGO exposure (4 h) but resensitized at a faster rate than MOR1 during agonist withdrawal (20 min). Immunocytochemical analysis revealed that DAMGO-induced internalization of MOR1B proceeded much faster than that of MOR1 followed by rapid recycling of the receptor to the cell surface. In addition, the greater resistance of MOR1B to homologous desensitization compared with MOR1 as well as MOR1B resensitization was abolished when receptor reactivation/recycling was blocked with monensin, an inhibitor of endosomal acidification. It is concluded that the sequence at the cytoplasmic tail of MOR1B facilitates clathrin-coated vesicle-mediated endocytosis which, in turn, promotes accelerated receptor reactivation. Taken together, our findings suggest that carboxyl-terminal splicing of the rat opioid receptor modulates agonist-induced internalization and receptor resensitization.Prolonged exposure of G protein-coupled receptors to agonists results in a rapid decrease of receptor responsiveness. It is now generally accepted that agonist-induced desensitization involves phosphorylation of intracellular receptor domains. Several kinases have been implicated in opioid receptor desensitization, including cAMP-dependent protein kinase (PKA), 1 protein kinase C (PKC), and calcium/calmodulin-dependent protein kinase II (CaM kinase II) (1-5). Specific phosphorylation sites have been localized in the third intracellular domain and at the carboxyl terminus, which play a critical role in homologous desensitization of the opioid receptor (6 -10). Following phosphorylation, the receptor is being targeted to the endocytotic machinery. A large body of evidence suggests that the main route of internalization of G protein-coupled receptors is via clathrin-coated pits and vesicles into early endosomes. Within the acidic environment of the endosomes, the ligand is effectively separated from the receptor which becomes dephosphorylated and thus resensitized. As a final step, the receptor recycles back to the cell surface (11).For the opioid receptor, desensitization seems to be regulated by CaM kinase II-mediated phosphorylation of two serine residues (Ser 261 /Ser 266 ) in the third intracellular loop (3, 9). Another important phosphorylation site of the opioid receptor is the threonine at position 394 in the carboxyl terminus. Indeed, we and others have recently observed that site-directed mutagenesis of Thr 394 to alanine profoundly delays DAMGOinduced desensitization, suggesting that this site may be a primary target for phosphorylation by GRKs upon agonist binding to the MOR1 (9, 10).We have previously shown, that the cytoplasmic tail of the rat opioid receptor undergoes alternati...

Lichen planus (LP) is a chronic inflammatory and immune-mediated disease that affects the skin, hair, nails and mucous membranes. Although there is a broad clinical spectrum of lichen planus manifestations, the skin and oral cavity remain the major sites of involvement. A group of European dermatologists with a long-standing interest and expertise in lichen planus has sought to define therapeutic guidelines for the management of patients with LP. The clinical features, diagnosis and possible medications that clinicians can use, in order to control the disease, will be reviewed in this manuscript.The revised final version of the lichen planus guideline was passed on to the European Dermatology Forum (EDF) for a final consensus with the European Academy of Dermatology and Venereology (EADV).

S100A7/Psoriasin, a member of the epidermal differentiation complex, is widely overexpressed in invasive ER-negative (ERα-) breast cancers. However, it has not been established whether S100A7 contributes to breast cancer growth or metastasis. Here, we report the consequences of its expression on inflammatory pathways that impact breast cancer growth. Overexpression of human S100A7 or its murine homolog mS100a7a15, enhanced cell proliferation and upregulated various pro-inflammatory molecules in ERα- breast cancer cells. To examine in vivo effects, we generated mice with an inducible form of mS100a7a15 (MMTV-mS100a7a15 mice). Orthotopic implantation of MVT-1 breast tumor cells into the mammary glands of these mice enhanced tumor growth and metastasis. Compared to uninduced transgenic control mice, the mammary glands of mice where mS100a7a15 was induced exhibited increased ductal hyperplasia and expression of molecules involved in proliferation, signaling, tissue remodeling and macrophage recruitment. Furthermore, tumors and lung tissues obtained from these mice showed further increases in pro-metastatic gene expression and recruitment of tumor-associated macrophages (TAMs). Notably, in vivo depletion of TAM inhibited the effects of mS100a7a15 induction on tumor growth and angiogenesis. Further, introduction of soluble hS100A7 or mS100a7a15 enhanced chemotaxis of macrophages via activation of RAGE receptors. In summary, our work employed a powerful new model system to demonstrate that S100A7 enhances breast tumor growth and metastasis by activating proinflammatory and metastatic pathways.

The antimicrobial peptides (AMP) psoriasin (S100A7) and koebnerisin (S100A15) are differently induced in psoriatic skin. They act synergistically as chemoattractants and "alarmins" to amplify inflammation in psoriasis. Th17 cytokines are key players in psoriasis pathogenesis and vitamin D analogs feature anti-psoriatic effects; both of these activities could be mediated through epidermal AMP regulation. We show that supernatants of cultured psoriatic T cells induce and release psoriasin and koebnerisin from keratinocytes and the Th17 cytokines IL-17A, tumor necrosis factor-α, and IL-22 differently regulate psoriasin and koebnerisin reflecting their distinct expression pattern in normal and psoriatic skin. IL-17A is the principal inducer of both S100 and their expression is further amplified by cooperating Th17 cytokines in the micromilieu of psoriatic skin. Increased extracellular psoriasin and koebnerisin also synergize as "alarmins" to prime epidermal keratinocytes for production of immunotropic cytokines that further amplify the inflammatory response. Treatment of psoriatic plaques with the vitamin D analog calcipotriol interferes with the S100-mediated positive feedback loop by suppressing the increased production of psoriasin and koebnerisin in psoriatic skin and their Th17-mediated regulation in epidermal keratinocytes. Thus, targeting the S100-amplification loop could be a beneficial anti-inflammatory approach in psoriasis and other inflammatory skin diseases.

S100A7 (psoriasin) and S100A15 (koebnerisin) were first identified in inflamed psoriatic skin. They are of major interest because of their putative functional roles in innate immunity, epidermal cell maturation, and epithelial tumorigenesis. Human S100A7 and S100A15 have lately evolved by gene duplications within the epidermal differentiation complex (chromosome 1q21) during primate evolution forming a novel S100 subfamily. Therefore, S100A7 and S100A15 are almost identical in sequence (>90%) and are difficult to discriminate. Despite their high homology, S100A7 and S100A15 are distinct in tissue distribution, regulation, and function, and thus, exemplary for the diversity within the S100 family. Their different properties are compelling reasons to discriminate S100A7 (psoriasin) and S100A15 (koebnerisin) in epithelial homeostasis, inflammation, and cancer.

In an effort to identify psoriasis-associated genes, we compared gene expression in normal and psoriatic skin, using differential display RT-PCR technique. Sequence analysis of a 650-bp cDNA fragment (clone 110) that was highly up-regulated in lesional skin revealed homology to a noncoding cDNA (NICE-2). By subsequent cDNA cloning, using RNA from psoriatic skin, we have identified two alternatively spliced mRNA-isoforms (0.5 and 4.4 kb), which differ in composition of their untranslated regions. By sequence comparison, we have mapped the novel gene, named S100A15, to the S100 gene cluster within the epidermal differentiation complex (chromosome 1q21). Analysis of the deduced amino acid sequence revealed a protein of 101 amino acids containing two potential EF-hand motifs with high homology to the S100A7. Northern blot hybridization and semiquantitative RT-PCR analysis confirmed the S100A15 overexpression in psoriasis, showing different levels of expression of the S100A15 mRNA isoforms. In situ hybridization of the S100A15 revealed a markedly increased staining of basal and suprabasal epidermal layers of psoriatic skin compared with healthy tissue. Our data suggest an involvement of the novel S100A15 in epidermal differentiation and inflammation and might therefore be important for the pathogenesis of psoriasis and other diseases.

Psoriasis is a common complex genetic disease characterized by hyperplasia and inflammation in the skin; however, the relative contributions of epidermal cells and the immune system to disease pathogenesis remain unclear. Linkage studies have defined a psoriasis susceptibility locus (PSORS4) on 1q21, the epidermal differentiation complex, which includes genes for small S100 calcium-binding proteins. These proteins are involved in extracellular and intracellular signaling during epithelial host defense, linking innate and adaptive immunity. Inflammation-prone psoriatic skin constitutively expresses elevated concentrations of S100A7 (psoriasin) and S100A15 (koebnerisin) in the epidermis. Here, we report that genetically modified mice expressing elevated amounts of doxycycline-regulated mS100a7a15 in skin keratinocytes demonstrated an exaggerated inflammatory response when challenged by exogenous stimuli such as abrasion (Koebner phenomenon). This immune response was characterized by immune cell infiltration and elevated concentrations of T helper 1 (T(H)1) and T(H)17 proinflammatory cytokines, which have been linked to the pathogenesis of psoriasis and were further amplified upon challenge. Both inflammation priming and amplification required mS100a7a15 binding to the receptor of advanced glycation end products (RAGE). mS100a7a15 potentiated inflammation by acting directly as a chemoattractant for leukocytes, further increasing the number of inflammatory cells infiltrating the skin. This study provides a pathogenetic psoriasis model using a psoriasis candidate gene to link the epidermis and innate immune system in inflammation priming, highlighting the S100A7A15-RAGE axis as a potential therapeutic target.