27 research outputs found
Genetically Programmed Differences in Epidermal Host Defense between Psoriasis and Atopic Dermatitis Patients
In the past decades, chronic inflammatory diseases such as psoriasis, atopic dermatitis, asthma, Crohn’s disease and celiac disease were generally regarded as immune-mediated conditions involving activated T-cells and proinflammatory cytokines produced by these cells. This paradigm has recently been challenged by the finding that mutations and polymorphisms in epithelium-expressed genes involved in physical barrier function or innate immunity, are risk factors of these conditions. We used a functional genomics approach to analyze cultured keratinocytes from patients with psoriasis or atopic dermatitis and healthy controls. First passage primary cells derived from non-lesional skin were stimulated with pro-inflammatory cytokines, and expression of a panel of 55 genes associated with epidermal differentiation and cutaneous inflammation was measured by quantitative PCR. A subset of these genes was analyzed at the protein level. Using cluster analysis and multivariate analysis of variance we identified groups of genes that were differentially expressed, and could, depending on the stimulus, provide a disease-specific gene expression signature. We found particularly large differences in expression levels of innate immunity genes between keratinocytes from psoriasis patients and atopic dermatitis patients. Our findings indicate that cell-autonomous differences exist between cultured keratinocytes of psoriasis and atopic dermatitis patients, which we interpret to be genetically determined. We hypothesize that polymorphisms of innate immunity genes both with signaling and effector functions are coadapted, each with balancing advantages and disadvantages. In the case of psoriasis, high expression levels of antimicrobial proteins genes putatively confer increased protection against microbial infection, but the biological cost could be a beneficial system gone awry, leading to overt inflammatory disease
Expression of the chemokine receptor CCR5 in psoriasis and results of a randomized placebo controlled trial with a CCR5 inhibitor
Several reports have indicated that the chemokine receptor CCR5 and its ligands, especially CCL5 (formerly known as RANTES), may play a role in the pathogenesis of psoriasis. The purpose of this investigation was to examine the expression of CCR5 and its ligands in chronic plaque psoriasis and to evaluate the clinical and immunohistochemical effect of a CCR5 receptor inhibitor. Immunohistochemical analysis showed low but significant increased total numbers of CCR5 positive cells in epidermis and dermis of lesional skin in comparison to non-lesional skin. However, relative expression of CCR5 proportional to the cells observed revealed that the difference between lesional and non-lesional skin was only statistically significant in the epidermis for CD3 positive cells and in the dermis for CD68 positive cells. Quantification of mRNA by reverse transcriptase-polymerase chain reaction only showed an increased expression of CCL5 (RANTES) in lesional skin. A randomized placebo-controlled clinical trial in 32 psoriasis patients revealed no significant clinical effect and no changes at the immunohistochemical level comparing patients treated with placebo or a CCR5 inhibitor SCH351125. We conclude that although CCR5 expression is increased in psoriatic lesions, this receptor does not play a crucial role in the pathogenesis of psoriasis
Transcriptomic analysis of the temporal host response to skin infestation with the ectoparasitic mite Psoroptes ovis
<p>Abstract</p> <p>Background</p> <p>Infestation of ovine skin with the ectoparasitic mite <it>Psoroptes ovis </it>results in a rapid cutaneous immune response, leading to the crusted skin lesions characteristic of sheep scab. Little is known regarding the mechanisms by which such a profound inflammatory response is instigated and to identify novel vaccine and drug targets a better understanding of the host-parasite relationship is essential. The main objective of this study was to perform a combined network and pathway analysis of the <it>in vivo </it>skin response to infestation with <it>P. ovis </it>to gain a clearer understanding of the mechanisms and signalling pathways involved.</p> <p>Results</p> <p>Infestation with <it>P. </it>ovis resulted in differential expression of 1,552 genes over a 24 hour time course. Clustering by peak gene expression enabled classification of genes into temporally related groupings. Network and pathway analysis of clusters identified key signalling pathways involved in the host response to infestation. The analysis implicated a number of genes with roles in allergy and inflammation, including pro-inflammatory cytokines (<it>IL1A, IL1B, IL6, IL8 </it>and <it>TNF</it>) and factors involved in immune cell activation and recruitment (<it>SELE, SELL, SELP, ICAM1, CSF2, CSF3, CCL2 </it>and <it>CXCL2</it>). The analysis also highlighted the influence of the transcription factors NF-kB and AP-1 in the early pro-inflammatory response, and demonstrated a bias towards a Th2 type immune response.</p> <p>Conclusions</p> <p>This study has provided novel insights into the signalling mechanisms leading to the development of a pro-inflammatory response in sheep scab, whilst providing crucial information regarding the nature of mite factors that may trigger this response. It has enabled the elucidation of the temporal patterns by which the immune system is regulated following exposure to <it>P. ovis</it>, providing novel insights into the mechanisms underlying lesion development. This study has improved our existing knowledge of the host response to <it>P. ovis</it>, including the identification of key parallels between sheep scab and other inflammatory skin disorders and the identification of potential targets for disease control.</p
Memantine inhibits ATP-dependent K+ conductances in dopamine neurons of the rat substantia nigra pars compacta
1-Amino-3,5-dimethyl-adamantane (memantine) is a noncompetitive
N-methyl-D-aspartate (NMDA) receptor antagonist
used in clinical practice to treat neurodegenerative disorders
that could be associated with excitotoxic cell death. Because
memantine reduces the loss of dopamine neurons of
the substantia nigra pars compacta (SNc) in animal models of
Parkinson’s disease, we examined the effects of this drug on
dopamine cells of the SNc. Besides inhibition of NMDA
receptor-mediated currents, memantine (30 and 100 M)
increased the spontaneous firing rate of whole-cell recorded
dopamine neurons in a midbrain slice preparation. Occasionally,
a bursting activity was observed. These effects were
independent from the block of NMDA receptors and were
prevented in neurons dialyzed with a high concentration of
ATP (10 mM). An increase in firing rate was also induced by
the ATP-sensitive potassium (KATP) channel antagonist tolbutamide
(300 M), and this increase occluded further effects
of memantine. In addition, KATP channel-mediated outward
currents, induced by hypoxia, were inhibited by
memantine (30 and 100 M) in the presence of the NMDA
receptor antagonist (5S,10R)-()-5-methyl-10,11-dihydro-
5H-dibenzo[a,d]cyclohepten-5,10-imine maleate (MK-801)
(10 M). An increase in the spontaneous firing rate by memantine
was observed in dopamine neurons recorded with
extracellular planar 8 8 multielectrodes in conditions of
hypoglycemia. These results highlight KATP channels as possible
relevant targets of memantine effects in the brain.
Moreover, in view of a proposed role of KATP conductances
in dopamine neuron degeneration, they suggest another
mechanism of action underlying the protective role of memantine
in Parkinson’s disease
H1 histamine receptor mediates inflammatory responses in human keratinocytes.
Background: Keratinocytes participate in initiation and. amplification of T-cell-mediated skin diseases. During these disorders, histamine can be released from both residents skin cells and immigrating leukocytes, and can affect the functions of dendritic cells, monocytes, and lymphocytes. Little information is available on the effects of histamine on keratinocytes. Objective: To examine the presence of functional H1 receptors on human keratinocytes and the capacity of histamine to modulate the expression of inflammatory molecules in these cells. Methods: Primary cultures of resting and cytokine-activated keratinocytes from healthy subjects were analyzed for histamine H1 receptor expression and the production of inflammatory mediators after exposure to histamine receptor agonists and antagonists. Results: Cultured keratinocytes constitutively expressed the H1 receptor mRNA and protein, which was not influenced by IFN-gamma, TNF-alpha, or IL-4. H1 but not H2 agonists induced calcium fluxes in keratinocytes. Treatment of keratinocytes with histamine (10(-7) to 10(-4) mol/L) or beta-histine increased the IFN-gamma-induced expression of membrane intercellular adhesion molecule 1 and MHC class I but not MHC class II molecules. Moreover, H1 stimulation promoted basal CC chemokine ligand (CCL)-5/RANTES and GM-CSF secretion and augmented IFN-gamma-induced release of the chemokines CCL2/monocyte chemoattractant protein 1, CCL5/RANTES, CCL20/macrophage inflammatory protein 3alpha, and CXC chemokine ligand 10/IFN-induced protein of 10 kd, as well as GM-CSF. Administration of the H1 antihistamine levocetirizine, but not of the H2 antihistamine cimetidine, abolished histamine-dependent expression of all of the investigated proinflammatory molecules in a dose-dependent manner (0.01-10 mumol/L). Levocetirizine at higher doses also reduced intercellular adhesion molecule 1, CCL5/RANTES, and GM-CSF release induced solely by IFN-gamma. Conclusion: Histamine exerts proinflammatory effects on keratinocytes via the H1 receptor, and these effects are efficiently inhibited by levocetrizine