Cell Adhesion Molecule E-cadherin Research Articles

Effect of Semen vaccariae and Taraxacu mogono on Cell Adhesion of Bovine Mammary Epithelial Cells

The aim of this study is to reveal the regulation mechanism of the effect of Semen vaccariae and Taraxacu mogono on the cell-cell adhersion molecule, E-cadherin and β-catenin on the proliferation role and secretion function of bovine mammary epithelial cells cultured in vitro. Firstly, the epithelial character of bovine mammary epithelial cells was authenticated using immunofluorescence, then the cell grow curve was observed and investigated after S. vaccariae and T. mogono treatment. On the effect of S. vaccariae and T. mogono, cell adhesion molecules E-cadherin, β-catenin and CycinD1 mRNA and protein were detected by qRT-PCR and Western blotting, respectively. The results showed that the cellular keratin 18 expressed positively and proliferated vigorously after S. vaccariae and T. mogono treament. The mRNA and protein levels of E-cadherin and CycinD1 were remarkably higher (P<0.05) in 36 h after S. vaccariae and T. mogono treatment. The cell proliferation at 36 h was increased significantly (P<0.05). In conclusion, S. vaccariae and T. mogono have a positive impact on the cell proliferation and an effect on the adhesion molecules E-cadherin, β-catenin and CycinD1 in the Wnt signaling pathway.

Wnt/beta-Catenin Signaling and Small Molecule Inhibitors

Wnt/β-catenin signaling is a branch of a functional network that dates back to the first metazoans and it is involved in a broad range of biological systems including stem cells, embryonic development and adult organs. Deregulation of components involved in Wnt/β-catenin signaling has been implicated in a wide spectrum of diseases including a number of cancers and degenerative diseases. The key mediator of Wnt signaling, β-catenin, serves several cellular functions. It functions in a dynamic mode at multiple cellular locations, including the plasma membrane, where β-catenin contributes to the stabilization of intercellular adhesive complexes, the cytoplasm where β-catenin levels are regulated and the nucleus where β-catenin is involved in transcriptional regulation and chromatin interactions. Central effectors of β-catenin levels are a family of cysteine-rich secreted glycoproteins, known as Wnt morphogens. Through the LRP5/6-Frizzled receptor complex, Wnts regulate the location and activity of the destruction complex and consequently intracellular β- catenin levels. However, β-catenin levels and their effects on transcriptional programs are also influenced by multiple other factors including hypoxia, inflammation, hepatocyte growth factor-mediated signaling, and the cell adhesion molecule E-cadherin. The broad implications of Wnt/β-catenin signaling in development, in the adult body and in disease render the pathway a prime target for pharmacological research and development. The intricate regulation of β-catenin at its various locations provides alternative points for therapeutic interventions.

Identification of germline mutations in the cancer predisposing gene CDH1 in patients with orofacial clefts

Orofacial clefts (OFC) are among the most common birth defects worldwide. The etiology of non-syndromic OFC is still largely unknown. During embryonic development, the cell adhesion molecule E-cadherin, encoded by CDH1, is highly expressed in the median edge epithelium of the palate. Furthermore, in multiple families with CDH1 mutations, OFC cases are observed. To determine whether CDH1 is a causative gene for non-syndromic OFC and to assess whether CDH1 mutation screening in non-syndromic OFC patients enables identification of families at risk of cancer, direct sequencing of the full coding sequence of CDH1 was performed in a cohort of 81 children with non-syndromic OFC. Eleven children had heterozygous CDH1 sequence variants, 5 cases with 4 distinct missense mutations and 8 cases with 4 intronic variants. Using a combination of in silico predictions and in vitro functional assays, three missense mutations in four non-syndromic OFC patients were predicted to be damaging to E-cadherin protein function. The intronic variants including one tested in an in vitro assay appeared to be benign, showing no influence on splicing. Functionally relevant heterozygous CDH1 missense mutations were found in 4 out of 81 (5%) patients with non-syndromic OFC. This finding opens a new pathway to reveal the molecular basis of non-syndromic OFC. Cancer risk among carriers of these mutations needs to be defined.

Effects of Arg–Gly–Asp-modified elastin-like polypeptide on pseudoislet formation via up-regulation of cell adhesion molecules and extracellular matrix proteins

Extracellular matrix (ECM) plays an important role in controlling the β-cell morphology, survival and insulin secretary functions. An RGD-modified elastin-like polypeptide (RGD-ELP), TGPG[VGRGD(VGVPG)6]20WPC, has been reported previously as a bioactive matrix. In this study, to investigate whether RGD-ELP affects β-cell growth characteristics and insulin secretion, β-TC6 cells were cultured on the RGD-ELP coatings prepared via thermally induced phase transition. On RGD-ELP, β-TC6 cells clustered into an islet-like architecture with high cell viability. Throughout 7days’ culture, the proliferation rate of the cells within a pseudoislet was similar to that of monolayer culture. Under high glucose (25mM), β-TC6 pseudoislets showed up-regulated insulin gene expression and exhibited glucose-stimulated insulin secretion. Importantly, the mRNA and protein abundances of cell adhesion molecules (CAM) E-cadherin and connexin-36 were much higher in pseudoislets than in monolayer cells. The siRNA-mediated inhibition of E-cadherin or connexin-36 expression severely limited pseudoislet formation. In addition, the mRNA levels of collagen types I and IV, fibronectin and laminin were significantly elevated in pseudoislets. The results suggest that RGD-ELP promotes pseudoislet formation via up-regulation of the CAM and ECM components. The functional roles of RGD-ELP are discussed in respect of its molecular composition.

The stability and activity of recombinant Helicobacter pylori HtrA under stress conditions

The bifunctional protein HtrA displays chaperone and protease activities, enabling bacteria to cope with environmental stress conditions such as heat shock or extreme pH by orchestrating protein folding or degradation. Recently, we added a novel aspect to HtrA functions by identifying HtrA of the human pathogen and class I carcinogen Helicobacter pylori (Hp) as a secreted virulence factor that cleaves the cell adhesion molecule and tumor suppressor E-cadherin. In this study, we analyzed the structural integrity and activity of oligomeric HtrA from Hp under stress conditions. Examining different parameters, HtrA oligomers were investigated by casein zymography and HtrA activity was further analyzed in in vitro cleavage assays using E-cadherin as a substrate. HtrA showed temperature-dependent disintegration of oligomers. Denaturing agents targeting hydrogen bonds within HtrA destabilized HtrA oligomers while reducing agents disrupting disulfide bonds had no effect. Optimal proteolytic activity was dependent on a neutral pH; however, addition of mono- and divalent salts or reducing agents did not interfere with proteolytic activity. These data indicate the HtrA is active under stress conditions which might support Hp colonizing in the gastric environment.

Sema4D, the Ligand for Plexin B1, Suppresses c-Met Activation and Migration and Promotes Melanocyte Survival and Growth

Semaphorins are secreted and membrane bound proteins involved in neural pathfinding, organogenesis, and tumor progression, through Plexin and neuropilins receptors. We recently reported that Plexin B1, the Semaphorin 4D receptor, is a tumor suppressor protein for melanoma, in part, through inhibition of the oncogenic c-Met tyrosine kinase receptor. In this report we show that Sema4D is a protective paracrine factor for normal human melanocyte survival in response to ultraviolet irradiation, that it stimulates proliferation, and regulates the activity of the c-Met receptor. c-Met receptor signaling stimulates melanocyte migration, in part through down-regulation of the cell adhesion molecule E-cadherin. Sema4D suppressed activation of c-Met in response to its ligand hepatocyte growth factor (HGF), and partially blocked the suppressive effects of HGF on E-cadherin expression in melanocytes and HGF-dependent migration. These data demonstrate a role for Plexin B1 in maintenance of melanocyte survival and proliferation in the skin, and suggest that Semaphorin 4D and Plexin B1 act cooperatively with HGF and c-Met to regulate c-Met dependent effects in human melanocytes. Because our data show that Plexin B1 is profoundly down-regulated by UVB in melanocytes, loss of Plexin B1 may accentuate HGF dependent effects on melanocytes, including melanocyte migration.

Loss of E-cadherin promotes the growth, invasion and drug resistance of colorectal cancer cells and is associated with liver metastasis

The recent studies indicated that the epithelial cell adhesion molecule E-cadherin is a well-recognized molecule that is important in cell adhesion. To further investigate the molecular basis of this notion, we used small-interfering RNA to inhibit E-cadherin function and found that loss of E-cadherin promoted Colorectal cancer cell growth, invasion and drug resistance through induction of β-catenin nuclear translocation and epithelial-to-mesenchymal transition. Further analysis of E-cadherin expression with clinicopathologic parameters showed that E-cadherin expression decreased in Colorectal cancer patients who developed liver metastasis (P = 0.043). These findings indicate that E-cadherin loss in tumors contributes to progression and metastatic dissemination. Thus, E-cadherin can act as a central modulator of the cell biological phenotypes and a potential prognostic marker in Colorectal cancer.

Wnt/beta-Catenin Signaling and Small Molecule Inhibitors

Wnt/β-catenin signaling is a branch of a functional network that dates back to the first metazoans and it is involved in a broad range of biological systems including stem cells, embryonic development and adult organs. Deregulation of components involved in Wnt/β-catenin signaling has been implicated in a wide spectrum of diseases including a number of cancers and degenerative diseases. The key mediator of Wnt signaling, β-catenin, serves several cellular functions. It functions in a dynamic mode at multiple cellular locations, including the plasma membrane, where β-catenin contributes to the stabilization of intercellular adhesive complexes, the cytoplasm where β-catenin levels are regulated and the nucleus where β-catenin is involved in transcriptional regulation and chromatin interactions. Central effectors of β-catenin levels are a family of cysteine-rich secreted glycoproteins, known as Wnt morphogens. Through the LRP5/6-Frizzled receptor complex, Wnts regulate the location and activity of the destruction complex and consequently intracellular β- catenin levels. However, β-catenin levels and their effects on transcriptional programs are also influenced by multiple other factors including hypoxia, inflammation, hepatocyte growth factor-mediated signaling, and the cell adhesion molecule E-cadherin. The broad implications of Wnt/β-catenin signaling in development, in the adult body and in disease render the pathway a prime target for pharmacological research and development. The intricate regulation of β-catenin at its various locations provides alternative points for therapeutic interventions.

Relevance of MET activation and genetic alterations of KRAS and E-cadherin for cetuximab sensitivity of gastric cancer cell lines

The therapeutic activity of the epidermal growth factor receptor (EGFR)-directed monoclonal antibody cetuximab in gastric cancer is currently being investigated. Reliable biomarkers for the identification of patients who are likely to benefit from the treatment are not available. The aim of the study was to examine the drug sensitivity of five gastric cancer cell lines towards cetuximab as a single agent and to establish predictive markers for chemosensitivity in this cell culture model. The effect of a combination of cetuximab with chemotherapy was compared between a sensitive and a nonsensitive cell line. EGFR expression, activation and localisation, the presence and subcellular localisation of the cell adhesion molecule E-cadherin as well as MET activation were examined by Western blot analysis, flow cytometry and immunofluorescence staining. Cells were treated with varying concentrations of cetuximab and cisplatin and 5-fluorouracil in tumour-relevant concentrations. The biological endpoint was cell viability, which was measured by XTT cell proliferation assay. Response to treatment was evaluated using statistical methods. We assessed the activity of cetuximab in five gastric cancer cell lines (AGS, KATOIII, MKN1, MKN28 and MKN45). The viability of two cell lines, MKN1 and MKN28, was significantly reduced by cetuximab treatment. High EGFR expression and low levels of receptor activation were associated with cetuximab responsiveness. MET activation as well as mutations of KRAS and CDH1 (gene encoding E-cadherin) was associated with cetuximab resistance. These data indicate that our examinations may be clinically relevant, and the candidate markers should therefore be tested in clinical studies.

Rosuvastatin-induced changes in mice kidney were remodeled by dietary essential amino acids supplementation

Rosuvastatin (Rvs) represents one of the most used cholesterol-lowering statins even if its effects may be wider than simply regulation of lipids metabolism [1]. Despite the efficacy in preventing cardiovascular diseases, long-term delivery of statins is associated to adverse effects [2]. So here we studied healthy normotensive mice fed with Rvs at a therapeutic dose (20 mg/kg/day) for one month. To evaluate the influence of dietary essential amino acids mixture (EAAm) in this model, other mice were fed with Rvs and EAAm daily for one month. A normal rodent chow or EAAm supplementation for the same period were further administered in control groups. Ultrastructural analysis of the glomerular filtration barrier did not show any difference between groups. Glomerular area together with mitochondria and lysosomal parameters in renal tubules were evaluated. Moreover we focused on the distribution of chaperones and mitochondria markers (Grp75, Grp78, Bcl2), nitric oxide isoforms (iNOS and eNOS), and cell adhesion molecules (E-cadherin and β-catenin). Control groups were similar except for increased mitochondria density and Grp75 staining after EAAm diet. In contrast, Rvs attenuated Grp75/Bcl2 patterns, but enhanced Grp78 expression. Remarkably E-cadherin shifted from the basolateral to the apical side in proximal tubules while evident β-catenin signal was maintained mainly in the distal tubules and in the macula densa. However, after one month of EAAm supplementation, all parameters become almost similar to controls, except for Bcl2 that persisted at higher level. These novel data suggest that, under basal conditions, Rvs may regulate proximal tubular polarity, lysosomes and mitochondria distribution. EAAm supplementation further reinforces the tubular structure in the kidney, stimulating mitochondriogenesis, as corroborated by morphometry, intense Bcl2 and vascular eNOS expressions. However to validate the efficacy of dietary of EAAm combined with Rvs therapy further studies on the renal function are mandatory.

Cdc6 licenses tumor growth

![Figure][1] Unlike control cells (left), cells that overexpress Cdc6 (right) lose E-cadherin (green) from the plasma membrane. Aprotein that permits cells to replicate their DNA also shuts down a tumor suppressor gene, [Sideridou et al.][2] report. The cell adhesion molecule E-cadherin

Recruitment of histone deacetylases HDAC1 and HDAC2 by the transcriptional repressor ZEB1 downregulates E-cadherin expression in pancreatic cancer

ObjectivePancreatic cancer is characterised by invasive tumour spread and early metastasis formation. During epithelial–mesenchymal transition, loss of the cell adhesion molecule E-cadherin is frequent and can be caused by genetic...

MTA1 of the MTA (metastasis-associated) gene family and its encoded proteins: molecular and regulatory functions and role in human cancer progression

MTA1 (a metastasis-associated gene) is a newly discovere d human gene (residing on chromsome 14q32.3) that belongs to a family of cancer progression-related genes ( MTA ). The mRNA product of MTA1 along with its protein product MTA1 have been reported to be over-expressed in a wide variety of animal and human tumors. For example, the expression of MTA1 and its encoded protein MTA1 correlates with the malignant properties of many human cancers, including cancers of the breast, colon, stomach, li ver, prostate and others. The MTA proteins have bee n shown to be ubiquitinated transcriptional co-repressors that fu nction in histone deacetylation and are part of the NuRD complex, a nucleosome remodeling and histone deacetylating complex whose stability appears to be regulated by ubi quitinated MTA1 binding to E3 ubiquitin ligase constitutive ph otomorphogenesis protein-1 (COP1). The MTA1 protein plays an essential role in c-MYC-mediated cell transformatio n, and its expression correlates with mammary gland tumor formation. In the latter, MTA1 helps convert mammary cells to more aggressive phenotypes by repression of the estrogen receptor (ER) via trans-activation through deacetylation of chromatin in the ER-responsive el ement of ERresponsive genes. Another member of the MTA family, MTA3, is induced by estrogen and represses the exp ression of the transcriptional repressor Snail, a master regul ator of epithelial to mesenchymal transformation, r esulting in the expression of the cell adhesion molecule E-cadherin and maintenance of a differentiated, normal epithel ial phenotype in mammary cells. An important activity mediated by both MTA1 and MTA2 is deacylation and inactivation of tumor suppressor p53protein, in part by controlling its s tability by inhibiting ubiquitination, leading to i nhibition of growth arrest and apoptosis. Another factor deacetylated a nd stabilized by MTA1 NuRD complex is hypoxia-inducible factor1α (HIF-1α), which is involved in angiogenesis. Therefore, th e MTA proteins represent a possible set of master c oregulatory molecules involved in the carcinogenesis and progression of various malignant tumors. As su ch, they could be important new tools for cancer diagnosis and tre atment.

Force via integrins but not E-cadherin decreases Oct3/4 expression in embryonic stem cells

Increasing evidence suggests that mechanical factors play a critical role in fate decisions of stem cells. Recently we have demonstrated that a local force applied via Arg-Gly-Asp (RGD) peptides coated magnetic beads to mouse embryonic stem (ES) cells increases cell spreading and cell stiffness and decreases Oct3/4 (Pou5f1) gene expression. However, it is not clear whether the effects of the applied stress on these functions of ES cells can be extended to natural extracellular matrix proteins or cell–cell adhesion molecules. Here we show that a local cyclic shear force applied via fibronectin or laminin to integrin receptors increased cell spreading and stiffness, downregulated Oct3/4 gene expression, and decreased cell proliferation rate. In contrast, the same cyclic force applied via cell–cell adhesion molecule E-cadherin (Cdh1) had no effects on cell spreading, Oct3/4 gene expression, and the self-renewal of mouse ES cells, but induced significant cell stiffening. Our findings demonstrate that biological responses of ES cells to force applied via integrins are different from those to force via E-cadherin, suggesting that mechanical forces might play different roles in different force transduction pathways to shape early embryogenesis.

Expression of e-cadherin, n-cadherin and snail and their correlation with clinicopathological variants: an immunohistochemical study of 132 invasive ductal breast carcinomas in Egypt

OBJECTIVE:To evaluate the expression of the cell adhesion molecules E-cadherin and N-cadherin and the transcription factor Snail in invasive ductal breast carcinomas and to determine their relationships with clinicopathological features.METHODS:Immunohistochemistry was used to examine E-cadherin, N-cadherin, and Snail protein expression in 132 invasive breast carcinomas.RESULTS:The expression of E-cadherin was decreased (negative or weak) in 37.1% of invasive carcinomas, while N-cadherin and Snail overexpression were detected in 51.9% and 40.9% of carcinomas, respectively. Low E-cadherin expression was significantly correlated with poorly differentiated carcinoma (53.1%), positive node status (80.9%), poor Nottingham Prognostic Index (64.7%), and the presence of estrogen and progesterone receptors. Overexpression of N-cadherin and Snail were also significantly correlated with poorly differentiated carcinoma, positive node status, and poor Nottingham Prognostic Index but were correlated with the absence of hormone receptors. Loss of E-cadherin immunoexpression was strongly associated with the presence of membranous N-cadherin (87.8%) and nuclear Snail (69.4%).CONCLUSION:Loss of E-cadherin and overexpression of N-cadherin and Snail in breast carcinomas may play a central role in the development of invasive ductal breast carcinoma. These biomarkers may provide a valuable reference for the study of invasive ductal carcinoma progression and to characterize the biological behavior of the tumor. In the future, increased N-cadherin and decreased E-cadherin expression may be used as indicators of the progression and prognosis of invasive ductal carcinoma.

Loss of E-cadherin expression and outcome among patients with resectable pancreatic adenocarcinomas

Only a minority of patients who undergo surgical resection for pancreatic ductal adenocarcinoma are cured. Since patient outcome is not reliably predicted using pathological factors (tumor stage, differentiation, and resection margin status) alone, markers of tumor behavior are needed. One candidate predictor of pancreatic cancer outcome is E-cadherin status. CDH1 is a tumor suppressor gene encoding an important cell adhesion molecule (E-cadherin). The aim of this study was to determine if, among patients undergoing pancreaticoduodenectomy for pancreatic adenocarcinoma, loss of E-cadherin expression was an independent predictor of poor outcome. We examined patterns of loss of E-cadherin by immunohistochemistry in tissue microarrays of 329 surgically resected pancreatic ductal adenocarcinomas. E-cadherin expression was then correlated with outcome. Kaplan–Meier analysis and Cox proportional hazards regression modeling were used to assess the mortality risk. One hundred forty-one pancreatic adenocarcinomas (43%) had partial or complete loss of E-cadherin expression within the analyzed tissue cores. In most instances (134 cases, 41%), this loss was partial. Patients whose pancreatic adenocarcinomas had either complete loss (n=7; median survival, 5.5 months) or partial loss (n=134; 12.7 months) of E-cadherin expression had significantly worse median survival than those with uniformly intact E-cadherin expression (n=188; 18.5 months) by univariate (P=0.002) and multivariate (P=0.006) analyses. In subgroup analysis, patients with poorly differentiated cancers had a worse prognosis if their cancers had partial loss of E-cadherin expression (P=0.02). Among patients undergoing pancreaticoduodenectomy for pancreatic ductal adenocarcinoma, partial loss of tumoral E-cadherin expression is an independent predictor of poor outcome.

E-Cadherin Acts as a Regulator of Transcripts Associated with a Wide Range of Cellular Processes in Mouse Embryonic Stem Cells

BackgroundWe have recently shown that expression of the cell adhesion molecule E-cadherin is required for LIF-dependent pluripotency of mouse embryonic stem (ES) cells.MethodologyIn this study, we have assessed global transcript expression in E-cadherin null (Ecad-/-) ES cells cultured in either the presence or absence of LIF and compared these to the parental cell line wtD3.ResultsWe show that LIF has little effect on the transcript profile of Ecad-/- ES cells, with statistically significant transcript alterations observed only for Sp8 and Stat3. Comparison of Ecad-/- and wtD3 ES cells cultured in LIF demonstrated significant alterations in the transcript profile, with effects not only confined to cell adhesion and motility but also affecting, for example, primary metabolic processes, catabolism and genes associated with apoptosis. Ecad-/- ES cells share similar, although not identical, gene expression profiles to epiblast-derived pluripotent stem cells, suggesting that E-cadherin expression may inhibit inner cell mass to epiblast transition. We further show that Ecad-/- ES cells maintain a functional β-catenin pool that is able to induce β-catenin/TCF-mediated transactivation but, contrary to previous findings, do not display endogenous β-catenin/TCF-mediated transactivation. We conclude that loss of E-cadherin in mouse ES cells leads to significant transcript alterations independently of β-catenin/TCF transactivation.

E‐cadherin is crucial for embryonic stem cell pluripotency and can replace OCT4 during somatic cell reprogramming

We report new functions of the cell-adhesion molecule E-cadherin in murine pluripotent cells. E-cadherin is highly expressed in mouse embryonic stem cells, and interference with E-cadherin causes differentiation. During cellular reprogramming of mouse fibroblasts by OCT4, SOX2, KLF4 and c-MYC, fully reprogrammed cells were exclusively observed in the E-cadherin-positive cell population and could not be obtained in the absence of E-cadherin. Moreover, reprogrammed cells could be established by viral E-cadherin in the absence of exogenous OCT4. Thus, reprogramming requires spatial cues that cross-talk with essential transcription factors. The cell-adhesion molecule E-cadherin has important functions in pluripotency and reprogramming.

Mutant p53 Disrupts MCF-10A Cell Polarity in Three-dimensional Culture via Epithelial-to-mesenchymal Transitions

Mutant p53 is not only deficient in tumor suppression but also acquires additional activity, called gain of function. Mutant p53 gain of function is recapitulated in knock-in mice that carry one null allele and one mutant allele of the p53 gene. These knock-in mice develop aggressive tumors compared with p53-null mice. Recently, we and others showed that tumor cells carrying a mutant p53 are addicted to the mutant for cell survival and resistance to DNA damage. To further define mutant p53 gain of function, we used the MCF-10A three-dimensional model of mammary morphogenesis. MCF-10A cells in three-dimensional culture undergo a series of morphological changes and form polarized and growth-arrested spheroids with hollow lumen, which resembles normal glandular architectures in vivo. Here, we found that endogenous wild-type p53 in MCF-10A cells was not required for acinus formation, but knockdown of endogenous wild-type p53 (p53-KD) led to partial clearance of cells in the lumen due to decreased apoptosis. Consistent with this, p53-KD altered expression patterns of the cell adhesion molecule E-cadherin, the cytoskeletal marker β-catenin, and the extracellular matrix protein laminin V. We also found that ectopic expression of the mutant G245S led to a phenotype similar to p53-KD, whereas a combination of ectopic expression of siRNA-resistant G245S with p53-KD led to a less cleared lumen. In contrast, ectopic expression of mutant R248W, R175H, and R273H disrupted normal acinus architectures with filled lumen and led to formation of irregular and multiacinus structures regardless of p53-KD. In addition, these mutants altered normal expression patterns and/or levels of E-cadherin, β-catenin, laminin V, and tight junction marker ZO-1. Furthermore, epithelial-to-mesenchymal transitions (EMT) markers, Snail, Slug, and Twist, were highly induced by mutant p53 and/or p53-KD. Together, we postulate that EMT represents a mutant p53 gain of function and mutant p53 alters cell polarity via EMT.

Delayed asthmatic response: a new phenotype of bronchial response to allergen challenge and soluble adhesion molecules in the serum

Patients with bronchial asthma develop various types of asthmatic response to bronchial challenge with allergen, such as immediate asthmatic response, late asthmatic response, or delayed asthmatic response (DYAR), due to different immunologic mechanisms. To investigate the appearance and possible changes in the concentrations of soluble cell adhesion molecules during the DYAR, to explore the involvement of particular cell types in the mechanism(s) leading to DYAR, and to contribute to a fuller understanding of this clinical phenomenon. The DYAR recorded in 28 patients (P < .001), appearing within 26 to 32 hours, reaching maximum within 32 to 48 hours, and resolving within 56 hours after the allergen challenge, was repeated 2 to 6 weeks later. The repeated DYAR (P < .001) was supplemented with blood cell counts and measurement of serum concentrations of soluble adhesion molecules by an enzyme-linked immunoassay. The prechallenge concentrations of soluble intercellular adhesion molecule 1 (sICAM-1), soluble vascular cell adhesion molecule 1 (sVCAM-1), soluble platelet endothelial cell adhesion molecule (sPECAM-1), soluble E-selectin, soluble L-selectin, soluble P-selectin, and soluble E-cadherin did not differ significantly from healthy controls. The DYAR was associated with the following changes in the serum: an increase of sICAM-1 at 6 and 12 hours and a decrease at 24 hours; an increase of sVCAM-1 at 24 and 36 hours; an increase of sPECAM-1 at 36 and 48 hours and a decrease at 56 and 72 hours; an increase of soluble E-selectin at 56 hours; an increase of soluble L-selectin at 56 and 72 hours; a decrease of soluble E-cadherin at 48 and 56 hours; and increased counts of blood leukocytes at 36, 48, and 56 hours, neutrophils at 24, 36, 48, and 56 hours, lymphocytes at 24, 36, and 48 hours, and monocytes at 6, 12, and 24 hours. The Th1/Th2 ratio in blood increased at 24, 36, 48, and 56 hours. The intracellular concentration of interferon γ, but not of interleukin 4, increased at 24, 36, 48, and 56 hours. These results provide evidence of the involvement of neutrophils, Th1 lymphocytes, monocytes, platelets, and endothelial cells, upon participation of various adhesion molecules, in mechanisms(s) underlying the clinical DYAR.