Altered Expression Of Adhesion Molecules Research Articles

Metformin Reduces the Progression of Atherogenesis by Regulating the Sestrin2-mTOR Pathway in Obese and Diabetic Rats.

In previous research, we found that Sestrin2 has a strong association with plasma atherogenicity and combats the progression of atherogenesis by regulating the AMPK-mTOR pathway. Metformin, an activator of AMPK, is widely used as a first-line therapy for diabetes, but its role in preventing atherosclerosis and cardiac outcomes is unclear. Hence, we aimed to assess the effect of metformin on preventing atherosclerosis and its regulatory role in the Sestrin2-AMPK -mTOR pathway in obese/diabetic rats. Animals were fed a high-fat diet to induce obesity, administered streptozotocin to induce diabetes, and then treated with metformin (150 mg/kg body weight) for 14 weeks. Aorta and heart tissues were analyzed for Sestrin2 status by western blotting and immunohistochemistry, AMPK and mTOR activities were investigated using western blotting, and atherogenicity-related events were evaluated using reverse transcription quantitative polymerase chain reaction and histology. Obese and diabetic rats showed significant decrease in Sestrin2 levels and AMPK activity, accompanied by increased mTOR activity in the heart and aorta tissues. Metformin treatment significantly restored Sestrin2 and AMPK levels, reduced mTOR activity, and restored the altered expression of inflammatory markers and adhesion molecules in obese and diabetic rats to normal levels. A histological analysis of samples from obese and diabetic rats showed atherosclerotic lesions both in aorta and heart tissues. The metformin-treated rats showed a decrease in atherosclerotic lesions, cardiac hypertrophy, and cardiomyocyte degeneration. This study presents further insights into the beneficial effects of metformin and its protective role against atherosclerosis through regulation of the Sestrin2-AMPK-mTOR pathway.

Effects of particulate matter on endothelial, epithelial and immune system cells

Particulate Matter (PM) is an air pollutant that is classified according to its aerodynamic diameter into particles with a diameter of less than 10 µm (PM10), a diameter of less than 2.5 µm (PM2.5), and particles ultra-fine with a diameter less than 0.1 µm (PM0.1). PM10 is housed in the respiratory system, while PM2.5 and 0.1 can pass into the circulation to generate systemic alterations. Although several diseases associated with PM exposure, such as respiratory, cardiovascular, and central nervous system, have been documented to cause 4.2 million premature deaths per year worldwide. Few reviews address cellular and molecular mechanisms in the epithelial and endothelial cells of the tissues exposed to PM, which can cause these diseases, this being the objective of the present review. For this, a search was carried out in the NCBI and Google Scholar databases focused on scientific publications that addressed the expression of pro-inflammatory molecules, adhesion molecules, and oxidative radicals, among others, and their relationship with the effects caused by the PM. The main findings include the increase in pro-inflammatory cytokines and dysfunction in the components of the immune response; the formation of reactive oxygen species; changes in epithelial and endothelial function, evidenced by altered expression of adhesion molecules; and the increase in molecules involved in coagulation. Complementary studies are required to understand the molecular effects of harmful health effects and the future approach to strategies to mitigate this response.

Interferon-γ Impairs Human Coronary Artery Endothelial Glucose Metabolism by Tryptophan Catabolism and Activates Fatty Acid Oxidation.

Endothelial cells depend on glycolysis for much of their energy production. Impaired endothelial glycolysis has been associated with various vascular pathobiologies, including impaired angiogenesis and atherogenesis. IFN-γ (interferon-γ)-producing CD4+ and CD8+ T lymphocytes have been identified as the predominant pathological cell subsets in human atherosclerotic plaques. Although the immunologic consequences of these cells have been extensively evaluated, their IFN-γ-mediated metabolic effects on endothelial cells remain unknown. The purpose of this study was to determine the metabolic consequences of the T-lymphocyte cytokine, IFN-γ, on human coronary artery endothelial cells. The metabolic effects of IFN-γ on primary human coronary artery endothelial cells were assessed by unbiased transcriptomic and metabolomic analyses combined with real-time extracellular flux analyses and molecular mechanistic studies. Cellular phenotypic correlations were made by measuring altered endothelial intracellular cGMP content, wound-healing capacity, and adhesion molecule expression. IFN-γ exposure inhibited basal glycolysis of quiescent primary human coronary artery endothelial cells by 20% through the global transcriptional suppression of glycolytic enzymes resulting from decreased basal HIF1α (hypoxia-inducible factor 1α) nuclear availability in normoxia. The decrease in HIF1α activity was a consequence of IFN-γ-induced tryptophan catabolism resulting in ARNT (aryl hydrocarbon receptor nuclear translocator)/HIF1β sequestration by the kynurenine-activated AHR (aryl hydrocarbon receptor). In addition, IFN-γ resulted in a 23% depletion of intracellular nicotinamide adenine dinucleotide in human coronary artery endothelial cells. This altered glucose metabolism was met with concomitant activation of fatty acid oxidation, which augmented its contribution to intracellular ATP balance by >20%. These metabolic derangements were associated with adverse endothelial phenotypic changes, including decreased basal intracellular cGMP, impaired endothelial migration, and a switch to a proinflammatory state. IFN-γ impairs endothelial glucose metabolism by altered tryptophan catabolism destabilizing HIF1, depletes nicotinamide adenine dinucleotide, and results in a metabolic shift toward increased fatty acid oxidation. This work suggests a novel mechanistic basis for pathological T lymphocyte-endothelial interactions in atherosclerosis mediated by IFN-γ, linking endothelial glucose, tryptophan, and fatty acid metabolism with the nicotinamide adenine dinucleotide balance and ATP generation and their adverse endothelial functional consequences.

Unique immune signatures predict potential cardiometabolic risk in severe COVID-19 patients and COVID-19 recovered individuals

Abstract Covid-19, the disease caused by SARS-CoV-2 infection, has resulted in millions of deaths and led to a global public health emergency. SARS-CoV-2 infected patients exhibit a wide variety of phasic clinical manifestations ranging from asymptomatic to severe complications and death. SARS-CoV-2 infection can lead to excessive immune activation, inflammation and multi-organ damage. Clinical data showed that COVID-19 may promote the development of cardiovascular disorders (CVDs). Immune activation, thrombosis, cytokine storm, and altered adhesion molecule expression on leukocyte populations have been proposed as possible mechanisms that trigger COVID-19 associated CVDs. A lack of systematic studies on how SARS-CoV-2 infection triggered immune responses that may lead to CVDs, hinder early risk identification and therapeutic interventions. In this study, by using deep immune profiling and extensive cytokine and chemokine profiling, we explore potential mechanisms of developing CVDs in severe COVID-19 patients (ICU) (n=20) as well as patients recovered from COVID-19 (RD) (n=30). We identify core immune signatures in ICU patients and RD compared to healthy controls (n=17) that may predict potential cardiovascular risk. We found that significantly elevated eosinophils and neutrophils and increased circulating levels of tissue factor, fatty acid binding protein 4 and, LPS binding protein in ICU patients suggested increased immune activation and thrombotic risk. Interestingly, we found significant elevation of several immune parameters (TIMP-1, TIMP-2, Monocytes) that were associated with cardiometabolic risk, in RD group. Thus, our data suggest a possible mechanistic link between severe COVID-19 and cardiometabolic risk.

MACC1 driven alterations in cellular biomechanics facilitate cell motility in glioblastoma

BackgroundMetastasis-associated in colon cancer 1 (MACC1) is an established marker for metastasis and tumor cell migration in a multitude of tumor entities, including glioblastoma (GBM). Nevertheless, the mechanism underlying the increased migratory capacity in GBM is not comprehensively explored.MethodsWe performed live cell and atomic force microscopy measurements to assess cell migration and mechanical properties of MACC1 overexpressing GBM cells. We quantified MACC1 dependent dynamics of 3D aggregate formation. For mechanistic studies we measured the expression of key adhesion molecules using qRT-PCR, and MACC1 dependent changes in short term adhesion to fibronectin and laminin. We then determined changes in sub-cellular distribution of integrins and actin in dependence of MACC1, but also in microtubule and intermediate filament organization.ResultsMACC1 increased the migratory speed and elastic modulus of GBM cells, but decreased cell-cell adhesion and inhibited the formation of 3D aggregates. These effects were not associated with altered mRNA expression of several key adhesion molecules or altered short-term affinity to laminin and fibronectin. MACC1 did neither change the organization of the microtubule nor intermediate filament cytoskeleton, but resulted in increased amounts of protrusive actin on laminin.ConclusionMACC1 overexpression increases elastic modulus and migration and reduces adhesion of GBM cells thereby impeding 3D aggregate formation. The underlying molecular mechanism is independent on the organization of microtubules, intermediate filaments and several key adhesion molecules, but depends on adhesion to laminin. Thus, targeting re-organization of the cytoskeleton and cell motility via MACC1 may offer a treatment option to impede GBM spreading.2KztNGD5eRtzxX41hNP-QCVideo

Correlation between immunohistochemical staining of CEACAM1 and clinicopathological findings in oral pre-neoplastic lesions and squamous cell carcinoma.

Squamous cell carcinoma of the oral cavity represents the sixth most common cancer worldwide and it is often preceded by pre-neoplastic lesions. Sometimes it is still difficult for pathologists to make objective differential diagnoses only on histological characteristics. Tumorigenesis is accompanied by altered expression of cell adhesion molecules, like carcinoembryonic antigen cell adhesion molecule (CEACAM)1. We wanted to investigative CEACAM1 in oral dysplastic lesions, carcinoma in situ (CIS) and oral squamous cell carcinoma (OSCC). We examined immunohistochemical CEACAM1 expression in 50 OSCC, 30 oral CIS and 40 pre-neoplastic lesions and assessed its correlation with clinical and pathological parameters. CEACAM1 was not expressed in normal mucosa, significantly expressed in CIS while it was negative in all the dysplastic lesions. In OSCC, high CEACAM1 expression was associated with tumor grade and inversely correlated with both overall and disease-specific 5-year survival. We showed that CEACAM1 expression is very dynamic: absent in dysplastic lesions, up-regulated in CIS and OSCC. We suggest that CEACAM1 could be a prognostic marker of OSCC and oral CIS. Our most important finding was that it could help pathologists diagnosing oral carcinoma in situ.

Altered Monocyte and Endothelial Cell Adhesion Molecule Expression Is Linked to Vascular Inflammation in Human Immunodeficiency Virus Infection.

Background.Human immunodeficiency virus (HIV)-infected individuals have increased risk for vascular thrombosis, potentially driven by interactions between activated leukocytes and the endothelium.Methods.Monocyte subsets (CD14+CD16−, CD14+CD16+, CD14DimCD16+) from HIV negative (HIV−) and antiretroviral therapy-treated HIV positive (HIV+) participants (N = 19 and 49) were analyzed by flow cytometry for adhesion molecule expression (lymphocyte function-associated antigen 1 [LFA-1], macrophage-1 antigen [Mac-1], CD11c/CD18, very late antigen [VLA]-4) and the fractalkine receptor (CX3CR1); these receptors recognize ligands (intercellular adhesion molecules [ICAMs], vascular cell adhesion molecule [VCAM]-1, fractalkine) on activated endothelial cells (ECs) and promote vascular migration. Plasma markers of monocyte (soluble [s]CD14, sCD163) and EC (VCAM-1, ICAM-1,2, fractalkine) activation and systemic (tumor necrosis factor receptor [TNFR-I], TNFR-II) and vascular (lipoprotein-associated phospholipase A2 [Lp-PLA2]) inflammation were measured by enzyme-linked immunosorbent assay.Results.Proportions of CD16+ monocyte subsets were increased in HIV+ participants. Among all monocyte subsets, levels of LFA-1 were increased and CX3CR1 levels were decreased in HIV+ participants (P < .01). Levels of sCD163, sCD14, fractalkine, ICAM-1, VCAM-1, TNFR-II, and Lp-PLA2 were also increased in HIV+ participants (P < .05), and levels of sCD14, TNFR-I, and TNFR-II were directly related to ICAM-1 and VCAM-1 levels in HIV+ participants. Expression of CX3CR1 on monocyte subsets was inversely related to plasma Lp-PLA2 (P < .05 for all).Conclusions.Increased proportions of CD16+ monocytes, cells with altered adhesion molecule expression, combined with elevated levels of their ligands, may promote vascular inflammation in HIV infection.

Early Changes in Monocyte Adhesion Molecule Expression and Tumor Necrosis Factor-α Levels in Chronic Kidney Disease - A 5-Year Prospective Study

Background: Despite the absence of clinical symptoms, patients with chronic kidney disease (CKD) exhibit elevated levels of pro-inflammatory markers. To investigate whether it is possible to detect inflammatory activity and altered monocyte function at an early stage of renal disease, we studied patients with CKD stages 2-3 over 5 years. Methods: The expression of adhesion molecules on monocytes at resting state and after stimulation with formyl-methionyl-leucyl-phenylalanine (fMLP), as well as oxidative metabolism capacity was measured with flow cytometry in 108 CKD patients and healthy controls. Soluble markers of inflammation, such as cytokines, were analyzed using the Milliplex technique. Results: Patients showed significantly lower CD11b expression after stimulation during the 3rd (p = 0.002) and the 5th year (p < 0.001), together with a lower oxidative burst in response to fMLP over time (p = 0.02). The expression of CD62L on resting monocytes was lower during the 3rd (p = 0.001) and the 5th (p = 0.001) year in patients. Levels of tumor necrosis factor-α and RANTES were significantly increased (p = 0.001, p = 0.006) and interleukin-12 levels were also higher in CKD patients during the 5th year (p = 0.007). Conclusion: Monocytes in CKD stages 2-3 show emerging functional abrasions, with altered adhesion molecule expression and impaired fMLP response. These findings suggest that a transformation of monocyte function occurs at an early phase of renal impairment and may together with increased plasma levels of pro-inflammatory cytokines contribute to the higher vulnerability of CKD patients to comorbidities, such as infections and cardiovascular disease.

How I treat extramedullary myeloma

AbstractExtramedullary myeloma (EMM) is defined by the presence of plasma cells (PCs) outside the bone marrow in a patient with multiple myeloma (MM). Using sensitive imaging techniques including magnetic resonance imaging and positron emission tomography/computed tomography, EMM may be found in up to 30% of MM patients across the overall disease course. The molecular mechanisms underlying the hematogenous spread of PCs outside the bone marrow are only partially known and involve hypoxia and an altered expression of adhesion molecules. Extramedullary disease is associated with adverse prognostic factors (ie, high lactate dehydrogenase level, 17p deletion, and high-risk gene expression profile). The prognosis of EMM is poor, and the median overall survival of patients who experience an extramedullary relapse is <6 months. The adverse prognosis is less pronounced in patients with bone-related plasmacytomas than in those with hematogenous EMM. EMM patients should be considered as having high-risk myeloma and treated accordingly. However, EMM clinical situations are extraordinarily heterogeneous, and their management is particularly challenging. In the present review, a case-and-comment format is used to describe our approach to the management of EMM.

Alternative Splicing in Adhesion- and Motility-Related Genes in Breast Cancer.

Breast cancer is the most common tumor and the second leading cause of cancer death among woman, mainly caused by the metastatic spread. Tumor invasiveness is due to an altered expression of adhesion molecules. Among them, semaphorins are of peculiar interest. Cancer cells can manipulate alternative splicing patterns to modulate the expression of adhesion- and motility-related molecules, also at the isoform level. In this study, combining RNA-Sequencing on MCF-7 to targeted experimental validations—in human breast cell lines and breast tumor biopsies—we identified 12 new alternative splicing transcripts in genes encoding adhesion- and motility-related molecules, including semaphorins, their receptors and co-receptors. Among them, a new SEMA3F transcript is expressed in all breast cell lines and breast cancer biopsies, and is translated into a new semaphorin 3F isoform. In silico analysis predicted that most of the new putative proteins lack functional domains, potentially missing some functions and acquiring new ones. Our findings better describe the extent of alternative splicing in breast cancer and highlight the need to further investigate adhesion- and motility-related molecules to gain insights into breast cancer progression.

Pathogenic Actions of Cell Adhesion Molecule 1 in Pulmonary Emphysema and Atopic Dermatitis.

Cell adhesion mediated by adhesion molecules is of central importance in the maintenance of tissue homeostasis. Therefore, altered expression of adhesion molecules leads to the development of various tissue disorders involving cell activation, degeneration, and apoptosis. Nevertheless, it still remains unclear what initiates the altered expression of adhesion molecules and how the subsequent pathological cascades proceed. In this regard, cell adhesion molecule 1 (CADM1) is one of the candidates that is involved in the development of pathological lesions; it is an intercellular adhesion molecule that is expressed in various types of cells such as pulmonary cells, neurons, and mast cells. Recent studies have revealed that alterations in the transcriptional or post-transcriptional expressions of CADM1 correlate with the pathogenesis of pulmonary diseases and allergic diseases. In this review, we specifically focus on how CADM1 is involved in the development of pathological lesions in pulmonary emphysema and atopic dermatitis.

Vasculopathy in scleroderma.

Systemic sclerosis (SSc) is a multisystem connective tissue disorder featured by vascular injury and fibrosis of the skin and various internal organs with autoimmune background. Although the pathogenesis of SSc still remains elusive, it is generally accepted that initial vascular injury due to autoimmunity and/or environmental factors causes structural and functional abnormalities of vasculature which eventually result in the constitutive activation of fibroblasts in various organs. Structural alterations consist of destructive vasculopathy (loss of small vessels) and proliferative obliterative vasculopathy (occlusion of arterioles and small arteries with fibro-proliferative change) caused by impaired compensatory vasculogenesis and angiogenesis. Impaired function of SSc vasculature includes the altered expression of cell adhesion molecules predominantly inducing Th2 and Th17 cell infiltration, endothelial dysfunction primarily due to the low availability of nitric oxide, the activated endothelial-to-mesenchymal transition leading to fibro-proliferative vascular change and tissue fibrosis, and the impaired coagulation/fibrinolysis system promoting the formation of intravascular fibrin deposits. Recent new insights into the therapeutic mechanisms of intravenous cyclophosphamide pulse and bosentan and the establishment of a new SSc animal model (Klf5 (+/-);Fli1 (+/-) mice) provide us useful clues to further understand the development of vascular alterations characteristic of SSc. This article overviewed the present understanding of the pathogenesis of SSc vasculopathy.

Fibroblasts as pathogenic cells in rheumatic inflammation

Rheumatoid arthritis (RA) is an autoimmune disease characterized by synovitis, synovial hyperplasia and progressive degeneration of affected joints. These processes are mediated by cells of the immune system as well as by synovial fibroblasts (RASF) originating from the lining layer of the synovium. In this scenario RASFs display an activated phenotype: they show an altered expression of adhesion molecules which allows attachment to articular cartilage and by synthesis of proteases they mediate progressive cartilage and bone destruction. Furthermore, they produce various cytokines and chemokines, which are essential for promoting the inflammatory response. In recent years it has become evident that RASFs not only passively respond to the proinflammatory milieu in the joints of RA patients but also actively contribute by the overproduction of several cytokines and chemokines. These proinflammatory cytokines trigger the transformation of RASFs into an aggressive and invasive phenotype. Additionally, the primarily altered genuine RASFs are actively involved in the recruitment and activation of immune cells. Taken together, they are key players in the development of the well-known chronic, destructive inflammatory response in joints affected by RA.

Altered Adhesion Molecule Expression of Leukocytes of SCD Patients in Crisis and Steady State

Background: Sickle cell disease (SCD) patients experience ischemic events resulting from vaso-occlusion of both macro-and microcirculation. A risk factor associated with increased morbidity and mortality is leukocytosis in the absence of infection. This study investigated the role of leukocytes in the pathogenesis of acute sickle cell crisis. Procedure: Children were enrolled at two tertiary care centers in three groups: hemoglobin SS (Hb SS) patients admitted to hospital with an acute crisis, non-crisis or steady state SS patients, and sickle cell screen negative, racematched controls. Flow cytometry measured cell surface expression of adhesion molecules. Results: 28 Hb SS and 10 control patients were enrolled. Elevated white blood and platelet counts were observed for the crisis children (P<0.01) compared to healthy control children. There was a significant increase in the expression of adhesion molecules on neutrophils and monocytes (CD11, CD 18 and CD-62L) in children in steady state (P<0.05) compared to crisis, and healthy children. 71% of crisis children were receiving non-steroidal anti-inflammatory drugs (NSAIDs) or hydroxycarbamide, whereas none of the patients in steady state were receiving these drugs. Conclusion: Further investigation is needed to explain these findings, but is likely due to the use of NSAIDs and hydroxycarbamide in our crisis patients.

Expression of short chain fatty acid receptors and pro-inflammatory cytokines in utero-placental tissues is altered in cows developing retention of fetal membranes

IntroductionRetention of fetal membranes (RFM) is an economically important condition in dairy cattle disturbing the health and production in affected animals. In spite of extensive research, pathogenesis for RFM and identification of a predictive marker for the condition still remains elusive. Since expulsion of fetal membranes in an inflammatory process, studying the expression of inflammatory molecules is expected to give an idea about the pathogenesis of RFM. MethodsExpression of pro-inflammatory cytokines, short chain fatty acid (SCFA) receptors and adhesion molecules was studied using qRT-PCR in the utero-placental tissues obtained from the cows that expelled fetal membranes normally (n = 12) and from the cows that developed RFM (n = 12). Concentrations of SCFAs were estimated in the utero-placental tissues using Gas Chromatography. ResultsThe concentration of butyrate in the utero-placental tissue extract was 3–4 times lower, and GPR41 and GPR43 mRNA expression was 7.7–10.0 and 3.4–4.4 folds lower (p < 0.05) in cows that developed RFM compared to those that expelled the fetal membranes normally. The expression of IL-1, IL-6, IL-8, TNF-α, ICAM and PECAM was higher (p < 0.05) in the cows that normally expelled the fetal membranes compared to those that developed RFM. DiscussionSince a clear association of butyrate levels, expression of pro-inflammatory cytokines, adhesion molecules and SCFAs receptors was observed with expulsion of fetal membranes, modulating the levels of these molecules prior to parturition might help in reducing the incidence of RFM in cows. ConclusionInflammatory response is essential for normal expulsion of fetal membranes and that inadequate or altered expression of pro-inflammatory cytokines, adhesion molecules and SCFA receptors is associated with RFM in cows.

Adhesion Molecule Expression and Function of Primary Endothelial Cells in Benign and Malignant Tissues Correlates with Proliferation

BackgroundComparative analysis of the cellular biology of the microvasculature in different tissues requires the availability of viable primary endothelial cells (ECs). This study describes a novel method to isolate primary ECs from healthy organs, repair blastemas and tumors as examples of non-proliferating and proliferating benign and malignant tissues and their functional characterization.Methodology/Principal FindingsSingle cell suspensions from hearts, lungs, repair blastemas and tumors were incubated consecutively with an anti-CD31 antibody and magnetic micro-beads, coupled to a derivative of biotin and streptavidin, respectively. Following magnetic bead separation, CD31-positive ECs were released by biotin-streptavidin competition. In the absence of micro-beads, ECs became adherent to plastic surfaces. ECs from proliferating repair blastemas and tumors were larger and exhibited higher expression densities of CD31, CD105 and CD102 compared to those from non-proliferating normal tissues such as heart and lung. The expression density of CD34 was particularly high in tumor-derived ECs, and that of CD54 and CD144 in ECs of repair blastemas. Functionally, ECs of non-proliferating and proliferating tissues differed in their capacity to form tubes in matrigel and to align under flow conditions.Conclusions/SignificanceThis method provides a powerful tool to generate high yields of viable, primary ECs of different origins. The results suggest that an altered expression of adhesion molecules on ECs in proliferating tissues contribute to loss of EC function that might cause a chaotic tumor vasculature.

Adhesion Molecules in Primary Oral Mucosal Melanoma

Primary oral mucosal melanoma is a rare aggressive tumor. Recent studies have demonstrated a correlation between increased tumor invasion and the metastatic phenotype and altered adhesion molecule expression profiles. The present study analyzed the expression of integrins, claudins, and immunoglobulin-like adhesion molecules in oral mucosal melanomas and correlated results with clinical parameters. Immunohistochemical analyses of the expression patterns of these molecules were performed on thirty-five cases of primary oral mucosal melanomas organized in a tissue microarray. The results were correlated with clinical and histological features of the cohort. A number of integrin subunits were negative and this was related with vascular invasion. Positivity of integrin beta-3 and CD166 (activated leukocyte cell adhesion molecule) was statistically associated with extensive vascular invasion (P < 0.05). Lower expression of CD54 (intercellular cell adhesion molecule) was associated with cases with extensive necrosis. Most cases with metastatic disease were negative for CD66 (carcinoembryonic antigen-related cell adhesion molecule). Several subunits of claudins were negative and, although not statistically significant, this lack of expression was partially associated with histological factors of poor prognosis. Altered patterns of adhesion molecule expression, mainly integrins and immunoglobulin-like proteins, may participate in the pathogenesis and outcome of oral mucosal melanomas.

Expression and Function of the Homeostatic Molecule Del-1 in Endothelial Cells and the Periodontal Tissue

Developmental endothelial locus-1 (Del-1) is an endothelial cell-secreted protein that limits the recruitment of neutrophils by antagonizing the interaction between the LFA-1 integrin on neutrophils and the intercellular adhesion molecule (ICAM)-1 on endothelial cells. Mice with genetic or age-associated Del-1 deficiency exhibit increased neutrophil infiltration in the periodontium resulting in inflammatory bone loss. Here we investigated additional novel mechanisms whereby Del-1 could interfere with neutrophil recruitment and inflammation. Treatment of human endothelial cells with Del-1 did not affect the expression of endothelial molecules involved in the leukocyte adhesion cascade (ICAM-1, VCAM-1, and E-selectin). Moreover, genetic or age-associated Del-1 deficiency did not significantly alter the expression of these adhesion molecules in the murine periodontium, further ruling out altered adhesion molecule expression as a mechanism whereby Del-1 regulates leukocyte recruitment. Strikingly, Del-1 inhibited ICAM-1-dependent chemokine release (CXCL2, CCL3) by neutrophils. Therefore, Del-1 could potentially suppress the amplification of inflammatory cell recruitment mediated through chemokine release by infiltrating neutrophils. Interestingly, Del-1 was itself regulated by inflammatory stimuli, which generally exerted opposite effects on adhesion molecule expression. The reciprocal regulation between Del-1 and inflammation may contribute to optimally balance the protective and the potentially harmful effects of inflammatory cell recruitment.

Extra domain A-positive fibronectin-positive feedback loops and their association with cutaneous inflammatory disease

Cutaneous inflammation can show Th1 or Th2 predominance, but the precise mechanisms by which such selectivity is determined are unknown. A recent study has demonstrated that Th1 cells, but not Th2 cells, produce an endogenous ligand for Toll-like receptor (TLR) 4, namely extradomain A+ fibronectin containing extra type III domain A (FnEDA+). As TLR4 stimulation leads to production of proinflammatory cytokines that recruit (via altered endothelial adhesion molecule expression and chemokine production) more Th1/Th17 cells, a positive feedback mechanism for Th1/Th17 inflammation exists. We propose that FnEDA+ positive feedback loops are a potential driver of Th1/Th17 inflammation. Conversely, the inflammatory EDA+ fibronectin loop is negatively regulated in atopic dermatitis, Th2 cytokines actively suppress TLR4 expression of Th1 cytokines, and recruited Th2 cells do not produce FnEDA+. In psoriasis, there are multiple FnEDA+ loops, comprising inflammatory, keratinocyte, and autoimmune loops. In allergic contact dermatitis, a single inflammatory loop operates. In atopic dermatitis, the FnEDA+ loop is actively suppressed by Th2 cytokines, and recruited Th2 cells do not “feedback” FnEDA+. We review endogenous ligands for TLR in relation to inflammatory disease, FnEDA+ function, and the potential role for FnEDA+ in psoriasis, allergic contact dermatitis, and atopic dermatitis.

Dupuytren's: a systems biology disease.

Dupuytren's disease (DD) is an ill-defined fibroproliferative disorder of the palm of the hands leading to digital contracture. DD commonly occurs in individuals of northern European extraction. Cellular components and processes associated with DD pathogenesis include altered gene and protein expression of cytokines, growth factors, adhesion molecules, and extracellular matrix components. Histology has shown increased but varying levels of particular types of collagen, myofibroblasts and myoglobin proteins in DD tissue. Free radicals and localised ischaemia have been suggested to trigger the proliferation of DD tissue. Although the existing available biological information on DD may contain potentially valuable (though largely uninterpreted) information, the precise aetiology of DD remains unknown. Systems biology combines mechanistic modelling with quantitative experimentation in studies of networks and better understanding of the interaction of multiple components in disease processes. Adopting systems biology may be the ideal approach for future research in order to improve understanding of complex diseases of multifactorial origin. In this review, we propose that DD is a disease of several networks rather than of a single gene, and show that this accounts for the experimental observations obtained to date from a variety of sources. We outline how DD may be investigated more effectively by employing a systems biology approach that considers the disease network as a whole rather than focusing on any specific single molecule.