Cell Communication and Adhesion最新文献

Bradykinin-related peptides (kinins) are well known to contribute to leukocyte recruitment to inflammatory foci; however, a role of these universal pro-inflammatory mediators in the first step of this process, i.e. the leukocyte adhesion to endothelial cells, is not well understood. In this work we found that bradykinin and des-Arg10-kallidin enhance the adhesion of polymorphonuclear bloods cells (PMN) to fibrinogen and fibronectin. Also, the PMN adherence to endothelial cells of HMEC-1 line strongly increased after stimulation by kinins, particularly des-Arg10-kallidin, or when PMN were co-stimulated with bradykinin and interleukin-1β. These effects were attenuated after PMN treatment with a specific inhibitor of carboxypeptidases, which convert kinins to their des-Arg metabolites. The kinin peptides were also able to change the Mac-1 integrin expression on the PMN surface. These results suggest a regulatory effect of kinins on leukocyte adhesion to endothelial wall, providing new aspects of the leukocyte infiltration into inflamed tissues.

Unlabelled: Gαq-stimulation reduces intercellular coupling within 10 min via a decrease in the membrane lipid phosphatidylinositol-4,5-bisphosphate (PIP2), but the mechanism is unknown. Here we show that uncoupling in rat cardiomyocytes after stimulation of α-adrenergic Gαq-coupled receptors with norepinephrine is prevented by proteasomal and lysosomal inhibitors, suggesting that internalization and possibly degradation of connexin43 (Cx43) is involved. Uncoupling was accompanied by increased Triton X-100 solubility of Cx43, which is considered a measure of the non-junctional pool of Cx43. However, inhibition of the proteasome and lysosome further increased solubility while preserving coupling, suggesting that communicating gap junctions can be part of the soluble fraction. Ubiquitination of Cx43 was also increased, and Cx43 co-immunoprecipitated with the ubiquitin ligase Nedd4.

Conclusions: Norepinephrine increases ubiquitination of Cx43 in cardiomyocytes, possibly via Nedd4. We suggest that Cx43 is subsequently internalized, which is preceded by acquired solubility in Triton X-100, which does not lead to uncoupling per se.

During development, epicardial cells act as progenitors for a large fraction of non-myocyte cardiac cells. Expression and function of molecules of the desmosome in the postnatal epicardium has not been studied. The objective of this study was to assess the expression of desmosomal molecules, and the functional importance of the desmosomal protein plakophilin-2 (PKP2), in epicardial and epicardium-derived cells. Epicardial explants were obtained from neonatal rat hearts. Presence of mechanical junction proteins was assessed by immunocytochemistry. Explants after PKP2 knockdown showed increased abundance of alpha smooth muscle actin-positive cells, increased abundance of lipid markers, enhanced cell migration velocity and increased abundance of a marker of cell proliferation. We conclude that a population of non-excitable, cardiac-resident cells express desmosomal molecules and, in vitro, show functional properties (including lipid accumulation) that depend on PKP2 expression. The possible relevance of our data to the pathophysiology of arrhythmogenic right ventricular cardiomyopathy, is discussed.

Natural Killer (NK)-cells are peripheral blood lymphocytes that represent an important arm of the innate immune system. NK-cells play a critical role in the immune surveillance against tumors and virally infected cells in a major histocompatibiliy complex (MHC)-unrestricted fashion. We have explored such capacities of NK-cells after differentiation from hematopoietic stem and progenitor cells derived from human umbilical cord blood. Several culture conditions have been established supporting proliferation and subsequent differentiation of these cells in terms of receptor expression and specific lysis depending on the growth conditions in the presence and absence of supportive stromal feeders. We show that acquisition of Killer Immunoglobulin Receptor (KIR) as well as NK Cytotoxicity Receptor expressions is independent of culture condition whereas absence of stromal feeders did not support acquisition of CD94/NKG2A expression. Such KIR-positive/NKG2A-negative cells generated under different culture conditions showed strong and specific cytolytic activity which could have impact on further immunotherapeutic strategies.

Adult stem cell niches are characterized by a dichotomy of cycling and quiescent stem cells: while the former are responsible for tissue turnover, their quiescent counterparts are thought to become active upon tissue injury thus underlying the regenerative response. Moreover, quiescence prevents adult stem cells from accumulating mutations thus ensuring a reservoir of unaltered stem cells. In the intestine, while cycling stem cells were shown to give rise to the main differentiated lineages, the identity of their quiescent equivalents remains to date elusive. This is of relevance for conditions such as Crohn's disease and ulcerative colitis where quiescent stem cells may underlie metaplasia and the increased cancer risk associated with chronic inflammation. Tumours are thought to share a comparable hierarchical structure of adult tissues with pluripotent and self-renewing cancer stem cells (CSCs) giving rise to more differentiated cellular types. As such, neoplastic lesions may encompass both cycling and quiescent CSCs. Because of their infrequent cycling, quiescent CSCs are refractory to chemo- and radiotherapy and are likely to play a role in tumour dissemination, dormancy and recurrence.

The development of adhesion bonds, either among cells or among cells and components of the extracellular matrix, is a crucial process. These interactions are mediated by some molecules collectively known as adhesion molecules (CAMs). CAMs are ubiquitously expressed proteins playing a central role in controlling cell migration, proliferation, survival, and apoptosis. Besides their key function in physiological maintenance of tissue integrity, CAMs play an eminent role in various pathological processes such as cardiovascular disorders, atherogenesis, atherosclerotic plaque progression and regulation of the inflammatory response. CAMs such as selectins, integrins, and immunoglobulin superfamily take part in interactions between leukocyte and vascular endothelium (leukocyte rolling, arrest, firm adhesion, migration). Experimental data and pathologic observations support the assumption that pathogenic microorganisms attach to vascular endothelial cells or sites of vascular injury initiating intravascular infections. In this review a paradigm focusing on cell adhesion molecules pathophysiology and infective endocarditis development is given.

Cyclooxygenase (COX)-2 is a key molecular target of colon cancer prevention. However, the mechanisms by which COX-2 inhibitors confer protective effects against tumour development are not completely understood. The aim of this study was to elucidate the effects of NS-398 in the 1,2-dimethylhydrazine (DMH) mouse model with respect to alteration in the expression of COX-2 and E-cadherin-catenin complex. Alterations in cell proliferation, apoptosis, and vascular density were investigated. NS-398 showed reduced COX-2 immunoreactivity in adenomas with a decrease in vascular density in non-dysplastic mucosa. Adenomas revealed increased E-cadherin and beta-catenin reactivity. NS-398 reduced the percentages of tumour cells with nuclear localisation of beta-catenin and cyclin D1. Bromodeoxyuridine (BrdUrd) index in adenomas was significantly higher in untreated animals. NS-398 resulted in significant increase in apoptosis in adenomas. Our results suggest a protective role of NS-398 on tumour development associated with reduced COX-2 expression, reduced vascular density and perturbation of beta-catenin signalling pathway.

The traditional classification of signalling in biological systems is insufficient and outdated and novel efforts must take into account advances in systems theory, information theory and linguistics. We present some of the classification systems currently used both within and outside of the biological field and discuss some specific aspects of the nature of signalling in tissue development. The analytical methods used in understanding non-biological networks provide a valuable vocabulary, which requires integration and a system of classification to further facilitate development.

Homophilic binding of the neural cell adhesion molecule (NCAM) results in intracellular signaling, which also involves heterophilic engagement of coreceptors such as the fibroblast growth factor receptor (FGFR) and receptor protein tyrosine phosphatase-α (RPTPα). NCAM's own cellular dynamic itinerary includes endocytosis and recycling to the plasma membrane. Recent works suggest that NCAM could influence the trafficking of other receptor molecules that it associates with, particularly the FGFR. Furthermore, it was demonstrated that NCAM could undergo proteolytic processing upon activation. A processed fragment of NCAM, together with an N-terminal fragment of focal adhesion kinase (FAK), is translocated into the nucleus. Here, the authors discuss these rather unique (though not without precedence and analogues) receptor trafficking activities that are associated with NCAM and NCAM signaling.

Mucus hypersecretion is commonly observed in many chronic airway inflammatory diseases. Mucin 5AC (MUC5AC) is a major airway mucin because of its high expression in goblet cells. Here, the authors identified a gene called SAM domain-containing prostate-derived Ets factor (SPDEF) that was induced by interleukin (IL)-13. Their results showed that specific knockdown of SPDEF reduced IL-13-induced MUC5AC expression in human airway epithelial cells. This finding was associated with decreased expression of anterior gradient 2 (AGR2) and Ca(2+)-activated Cl(-) channel (CLCA1), which regulate IL-13-mediated MUC5AC overproduction. Furthermore, transfection with SPDEF siRNA enhanced expression of forkhead box a2 (Foxa2), a key transcription factor that is known to prevent mucus production. The authors also demonstrated that the repression of STAT6 inhibited expression of SPDEF and MUC5AC induced by IL-13. These results show that SPDEF plays a critical role in regulating a transcriptional network mediating IL-13-induced MUC5AC synthesis dependent on STAT6.