The IUPHAR/BPS Guide to PHARMACOLOGY (GtoPdb, www.guidetopharmacology.org) and its precursor IUPHAR-DB, have captured expert-curated interactions between targets and ligands from selected papers in pharmacology and drug discovery since 2003. This resource continues to be developed in conjunction with the International Union of Basic and Clinical Pharmacology (IUPHAR) and the British Pharmacological Society (BPS). As previously described, our unique model of content selection and quality control is based on 96 target-class subcommittees comprising 512 scientists collaborating with in-house curators. This update describes content expansion, new features and interoperability improvements introduced in the 10 releases since August 2015. Our relationship matrix now describes ∼9000 ligands, ∼15 000 binding constants, ∼6000 papers and ∼1700 human proteins. As an important addition, we also introduce our newly funded project for the Guide to IMMUNOPHARMACOLOGY (GtoImmuPdb, www.guidetoimmunopharmacology.org). This has been ‘forked’ from the well-established GtoPdb data model and expanded into new types of data related to the immune system and inflammatory processes. This includes new ligands, targets, pathways, cell types and diseases for which we are recruiting new IUPHAR expert committees. Designed as an immunopharmacological gateway, it also has an emphasis on potential therapeutic interventions.

Reactive oxygen species (ROS) and mitochondria play an important role in apoptosis induction under both physiologic and pathologic conditions. Interestingly, mitochondria are both source and target of ROS. Cytochrome c release from mitochondria, that triggers caspase activation, appears to be largely mediated by direct or indirect ROS action. On the other hand, ROS have also anti-apoptotic effects. This review focuses on the role of ROS in the regulation of apoptosis, especially in inflammatory cells.

Despite recent advances in understanding microbial diversity in skin homeostasis, the relevance of microbial dysbiosis in inflammatory disease is poorly understood. Here we perform a comparative analysis of skin microbial communities coupled to global patterns of cutaneous gene expression in patients with atopic dermatitis or psoriasis. The skin microbiota is analysed by 16S amplicon or whole genome sequencing and the skin transcriptome by microarrays, followed by integration of the data layers. We find that atopic dermatitis and psoriasis can be classified by distinct microbes, which differ from healthy volunteers microbiome composition. Atopic dermatitis is dominated by a single microbe (Staphylococcus aureus), and associated with a disease relevant host transcriptomic signature enriched for skin barrier function, tryptophan metabolism and immune activation. In contrast, psoriasis is characterized by co-occurring communities of microbes with weak associations with disease related gene expression. Our work provides a basis for biomarker discovery and targeted therapies in skin dysbiosis.

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Nerve growth factor (NGF) is a polypeptide which, in addition to its effect on nerve cells, is believed to play a role in inflammatory responses and in tissue repair. Because fibroblasts represent the main target and effector cells in these processes, to investigate whether NGF is involved in lung and skin tissue repair, we studied the effect of NGF on fibroblast migration, proliferation, collagen metabolism, modulation into myofibroblasts, and contraction of collagen gel. Both skin and lung fibroblasts were found to produce NGF and to express tyrosine kinase receptor (trkA) under basal conditions, whereas the low-affinity p75 receptor was expressed only after prolonged NGF exposure. NGF significantly induced skin and lung fibroblast migration in an in vitro model of wounded fibroblast and skin migration in Boyden chambers. Nevertheless NGF did not influence either skin or lung fibroblast proliferation, collagen production, or metalloproteinase production or activation. In contrast, culture of both lung and skin fibroblasts with NGF modulated their phenotype into myofibroblasts. Moreover, addition of NGF to both fibroblast types embedded in collagen gel increased their contraction. Fibrotic human lung or skin tissues displayed immunoreactivity for NGF, trkA, and p75. These data show a direct pro-fibrogenic effect of NGF on skin and lung fibroblasts and therefore indicate a role for NGF in tissue repair and fibrosis.fibrosis ͉ migration ͉ trkA ͉ p75 ͉ gel contraction

Under physiological conditions, skin mast cells preferentially localize around nerves, blood vessels and hair follicles. This observation, which dates back to Paul Ehrlich, intuitively suggests that these enigmatic, multifacetted protagonists of natural immunity are functionally relevant to many more aspects of tissue physiology than just to the generation of inflammatory and vasodilatory responses to IgE-dependent environmental antigens. And yet, for decades, mainstream-mast cell research has been dominated by a focus on the -undisputedly prominent and important - mast cell functions in type I immune responses and in the pathogenesis and management of allergic diseases. Certainly, it is hard to believe that the very large and rather selectively distributed number of mast cells in normal, uninflamed, non-infected, non-traumatized mammalian skin or mucosal tissue simply hanging around there lazily day and night, just wait for the odd allergen or parasite-associated antigen to come by so the mast cell can finally swing into action. Indeed, the past decade has witnessed a renaissance of mast cell research 'beyond allergy', along with a more systematic exploration of the surprisingly wide range of physiological functions that mast cells may be involved in. The current debate sketches many exciting horizons that have recently come into our vision during this intriguing, ongoing search.

Eosinophils have been associated with fibrosis. To investigate their direct role in fibrosis, human peripheral blood eosinophil sonicate was added to human lung or dermal fibroblasts, and proliferation ([ 3 H]thymidine) and collagen synthesis ([ 3 H]proline) were evaluated. Proliferation was enhanced significantly in the monolayers in a dosedependent manner. The activity of the eosinophil fibrogenic factor(s) remained unaltered when heated (56°C, 30 min). Supernatants of cultured eosinophils (20 min or 18 hr) also enhanced lung fibroblast proliferation, indicating that the preformed mitogenic factor(s) can be released both promptly and with a long kinetic. Eosinophils significantly decreased collagen production in lung fibroblasts while increasing it in dermal fibroblasts. However, eosinophils containing matrix metalloproteinase 9 (zymography) in latent form and tissue inhibitors of metalloproteinases 1 and 2 (reverse zymography) did not inf luence either fibroblast matrix metalloproteinases or tissue inhibitors of metalloproteinases. Eosinophil sonicate added to skin and lung fibroblasts in tridimensional collagen lattices significantly enhanced lattice contraction. Transforming growth factor ␤ (TGF-␤) is a major fibrogenic cytokine produced by eosinophils. Therefore, to assess its role, eosinophil sonicate was preincubated with anti-TGF-␤ neutralizing antibodies. This treatment partially inhibited proliferation of lung and collagen synthesis of dermal fibroblasts and suppressed the stimulation of lattice contraction, indicating the fibrogenic role of eosinophil-associated TGF-␤. In conclusion, we have shown that eosinophils act as direct modulatory cells in fibroblast proliferation, collagen synthesis, and lattice contraction, in part, through TGF-␤. These data corroborate the importance of eosinophils in skin and lung fibrosis.

IntroductionProlonged survival and activation of eosinophils are "hallmark" features of allergic diseases. 1,2 Eosinophils are also associated with host defense mechanisms in parasitic infestations, with a variety of idiopathic hypereosinophilic syndromes, and are implicated in the pathogenesis of some immunologic and malignant disorders. 3,4 Within cytoplasmic granules eosinophils store 4 types of specific cationic proteins and several cytokines. In addition, upon stimulation they can also synthesize lipid mediators and a number of cytokines and chemokines with proinflammatory, immunoregulatory, and profibrotic properties. 5 The activatory signaling pathways regulating the activities of the eosinophils have been extensively studied. [6][7][8][9][10][11] Surprisingly, the role of inhibitory signaling pathways that could restrain eosinophil activation has been scarcely examined. Recently, it has been reported that activation of human eosinophils by siglec-8, even in the presence of IL-5 or GM-CSF, the "eosinophil survival cytokines," inhibits their survival by inducing apoptosis. 12 Furthermore, Mig (CXCL9) by binding to CCR3 has been shown to block murine eosinophil chemotaxis and function. 13,14 Notably, the importance of defining new pathways that suppress eosinophil accumulation, survival, and activation has been recently bolstered by the demonstration of a critical role for eosinophils in allergicairway inflammation in 2 different eosinophil-deficient mice. 15,16 Inhibitory receptors have been characterized on cytotoxic T cells and natural killer (NK) cells and recognize diverse ligands such as major histocompatibility complex (MHC) class I molecules, adhesion molecules, or yet undefined ligands. 17,18 Two main families of inhibitory receptors exist. The immunoglobulin receptor (IgR) superfamily is characterized by V-type Ig-like domain(s) in their extracellular domain and includes receptors such as KIRs, LIRs/ILTs, siglecs, LAIR-1, gp49B1, and IRp60. The second superfamily of inhibitory receptors consists of the calciumdependent lectins such as MAFA or CD94/NKG2A. 19 Both families can be identified by a consensus amino acid sequence, the immunoreceptor tyrosine-based inhibitory motif (ITIM), which is present in the cytoplasmic domain of these molecules. The archetype ITIM sequence is composed of 6 amino acids (Ile/Val/Leu/ Ser)-X-Tyr-X-X-(Leu/Val), where X denotes any amino acid. Upon activation, these inhibitory receptors undergo tyrosine phosphorylation, often by a Src kinase, which provides a docking site for the recruitment of cytoplasmic phosphatases having a Src homology 2 (SH2) domain such as SHP-1, -2 and SHIP-1, -2. Recruitment of For personal use only. on May 10, 2018. by guest www.bloodjournal.org From SHP-1, -2 and/or SHIP-1, -2 results in upstream inhibition of cell activation before any signaling cascade has been initiated. [17][18][19] IRp60 is a non-MHC-specific inhibitory receptor belonging to the IgR superfamily. It is expressed on many cell types including T cells, NK cells, monocytes, an...