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1.
Chronic granulomatous disease is an inherited disorder of the NADPH oxidase characterized by severe bacterial and fungal infections
and disordered inflammation. We propose that NADPH oxidase has a key role in regulating acute neutrophilic and T cell responses,
which in turn restrains fungal growth and calibrates the inflammatory response to minimize injury and allergy. In this model,
superoxide-induced activation of indoleamine 2,3-dioxygenase (IDO) is a central mechanism by which the optimal balance of
antifungal host defense and immune tolerance occurs. This model is based on studies in mice and requires correlation in humans.
Received 18 August 2008; received after revision 29 November 2008; accepted 16 December 2008 相似文献
2.
Cell-cell adhesion is a critical property of all multi-cellular organisms and its correct regulation is critical during development,
differentiation, tissue building and maintenance, and many immune responses. The multi-talin-like FERM domain containing protein,
FrmA, is required during starvation-induced multi-cellular development of Dictyostelium cells. Loss of FrmA leads to increased cell-cell adhesion and results in impaired multi-cellular development, slug migration
and fruiting bodies. Further, mixing experiments show that FrmA null cells are excluded from the apex of wild-type mounds,
to which cells that normally form the organising centre known as the tip sort. These data suggest a critical role for FrmA
in regulating cell-cell adhesion, multi-cellular development and, in particular, the formation of the organising centre known
as the tip.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users.
Received 28 August 2008; received after revision 10 October 2008; accepted 21 October 2008 相似文献
3.
C. L. Salanga M. O’Hayre T. Handel 《Cellular and molecular life sciences : CMLS》2009,66(8):1370-1386
Chemokines are small, secreted proteins that bind to the chemokine receptor subfamily of class A G protein-coupled receptors.
Collectively, these receptor-ligand pairs are responsible for diverse physiological responses including immune cell trafficking,
development and mitogenic signaling, both in the context of homeostasis and disease. However, chemokines and their receptors
are not isolated entities, but instead function in complex networks involving homo- and heterodimer formation as well as crosstalk
with other signaling complexes. Here the functional consequences of chemokine receptor activity, from the perspective of both
direct physical associations with other receptors and indirect crosstalk with orthogonal signaling pathways, are reviewed.
Modulation of chemokine receptor activity through these mechanisms has significant implications in physiological and pathological
processes, as well as drug discovery and drug efficacy. The integration of signals downstream of chemokine and other receptors
will be key to understanding how cells fine-tune their response to a variety of stimuli, including therapeutics.
Received 19 October 2008; received after revision 7 November 2008; accepted 11 November 2008
C. L. Salanga, M. O’Hayre: These authors contributed equally. 相似文献
4.
Merkel cell carcinoma (MCC) is a highly aggressive neuroendocrine carcinoma of the skin. More than one-third of MCC patients
will die from this cancer, making it twice as lethal as malignant melanoma. Despite the fact that MCC is still a very rare
tumor, its incidence is rapidly increasing; the American Cancer Society estimates for 2008 almost 1 500 new cases in the USA.
These clinical observations are especially disturbing as the pathogenesis of MCC is not yet fully understood; however, a number
of recent reports contribute to a better understanding of its pathogenesis. Here we describe findings regarding the role of
Wnt, MAPK and Akt signaling as well as possible aberrations in the p14ARF/p53/RB tumor suppressor network in MCC. Most important,
and possibly with high impact on future therapeutic approaches is the demonstration that a polyomavirus has frequently integrated
in the genome of the MCC cells prior to tumor development.
Received 12 August 2008; received after revision 06 October 2008; accepted 22 October 2008 相似文献
5.
Novel regulation and function of Src tyrosine kinase 总被引:4,自引:0,他引:4
Src tyrosine kinase is a critical signal transducer that modulates a wide variety of cellular functions. Misregulation of
Src leads to cell transformation and cancer. Heterotrimeric guanine-nucleotide-binding proteins (G proteins) are another group
of signaling molecules that transduce signals from cell-surface receptors to generate physiological responses. Recently, it
was discovered that Gαs and Gαi could directly stimulate Src family tyrosine kinase activity. This novel regulation of Src
tyrosine kinase by G proteins provides insights into the adenylyl cyclase-independent signaling mechanisms involved in ligand-induced
receptor desensitization, internalization and other physiological processes.
Received 17 August 2001; received after revision 22 October 2001; accepted 24 October 2001 相似文献
6.
K. Mutyambizi C. L. Berger R. L. Edelson 《Cellular and molecular life sciences : CMLS》2009,66(5):831-840
Langerhans cells are immature skin-homing dendritic cells that furnish the epidermis with an immune surveillance system, and
translate information between the internal and external milieu. Dendritic cells, in particular Langerhans cells, are gaining
prominence as one of the potential principal players orchestrating the decision between immunity and tolerance. Langerhans
cells capture aberrant self-antigen and pathogen-derived antigen for display to the efferent immune response. Recent evidence
suggests redundancy in the antigen-presenting function of Langerhans cells, with dermal dendritic subsets capable of fulfilling
an analogous role. There is mounting evidence that Langerhans cells can cross-prime T cells to recognize antigens. Langerhans
cells are proposed to stimulate T regulatory cells, and are implicated in the pathogenesis of cutaneous T cell lymphoma.The
phenotype of Langerhans cells, which may be tolerogenic or immunogenic, appears to depend on their state of maturity, inciting
immunogen and cytokine environment, offering the potential for manipulation in immunotherapy.
Received 6 August 2008; received after revision 18 September 2008; accepted 13 October 2008 相似文献
7.
Protease-activated receptors (PARs) play a clear role in the burst of inflammatory reactions and immune responses. However,
for PAR-3, the most elusive member of the PAR family, the functional role is still largely unclear. It has been claimed that
PAR-3 does not signal autonomously, although the wide expression of human PAR-3 indicates its important physiological roles.
We demonstrate that in HEK-293 cells, stably transfected with human PAR-3, thrombin induced calcium signaling, IL-8 gene expression
and IL-8 release. We confirmed this finding using human lung epithelial and human astrocytoma cells that express endogenous
PAR-3. Moreover, thrombin exposure of HEK-293 cells resulted in ERK1/2 activation coinciding with IL-8 release. The effects
of thrombin were not dependent on PAR-1 activation, as confirmed by PAR-1 gene silencing. Thus, we propose that PAR-3 is able
to signal autonomously to induce IL-8 release mediated by ERK1/2 phosphorylation, which contributes actively to inflammatory
responses.
Received 9 December 2007; received after revision 16 January 2008; accepted 18 January 2008 相似文献
8.
Heparanase is the sole mammalian endoglycosidase that cleaves heparan sulfate, the key polysaccharide of the extracellular matrix and basement membranes. Enzymatic cleavage of heparan sulfate profoundly affects a variety of physiological and pathological processes, including morphogenesis, neovascularization, inflammation, and tumorigenesis. Critical involvement of heparanase in colorectal tumor progression and metastatic spread is widely documented; however, until recently a role for heparanase in the initiation of colon carcinoma remained underappreciated. Interestingly, the emerging data that link heparanase to chronic inflammatory bowel conditions, also suggest contribution of the enzyme to colonic tumor initiation, at least in the setting of colitis-associated cancer. Highly coordinated interplay between intestinal heparanase and immune cells (i.e., macrophages) preserves chronic inflammatory conditions and creates a tumor-promoting microenvironment. Here we review the action of heparanase in colon tumorigenesis and discuss recent findings, pointing to a role for heparanase in sustaining immune cell-epithelial crosstalk that underlies intestinal inflammation and the associated cancer. 相似文献
9.
Wang R Han G Wang J Chen G Xu R Wang L Li X Shen B Li Y 《Cellular and molecular life sciences : CMLS》2008,65(23):3851-3860
Interleukin (IL)-27 is an IL-12-related cytokine that can promote both anti- and pro-inflammatory immune responses. This study
investigated the potential role of IL-27 in autoimmune diabetes. We detected a high level of IL-27 in diabetic NOD mice. In
addition, blockade of IL-27 significantly delayed the onset of diabetic splenocyte-transferred diabetes, while IL-27-treated
diabetic splenocytes promoted the onset of the disease, compared with untreated controls. Furthermore, IL-27 up-regulated
pro-inflammatory cytokines IFN-γ and IL-17 and down-regulated anti-inflammatory cytokines IL-4, TGF-β, and IL-10 secreted
by diabetic splenocytes. These results demonstrate a pathogenic role of IL-27 in T cell-mediated autoimmune diabetes.
Received 02 September 2008; received after revision 27 September 2008; accepted 01 October 2008
R. Wang, G. Han: These authors contributed equally to this work. 相似文献
10.
Wolfs JL Comfurius P Bekers O Zwaal RF Balasubramanian K Schroit AJ Lindhout T Bevers EM 《Cellular and molecular life sciences : CMLS》2009,66(2):314-323
The exposure of phosphatidylserine (PS) at the cell surface plays a critical role in blood coagulation and serves as a macrophage
recognition moiety for the engulfment of apoptotic cells. Previous observations have shown that a high extracellular [K+] and selective K+ channel blockers inhibit PS exposure in platelets and erythrocytes. Here we show that the rate of PS exposure in erythrocytes
decreases by ~50% when the intracellular [K+] increases from 0 to physiological concentrations. Using resealed erythrocyte membranes, we further show that lipid scrambling
is inducible by raising the intracellular [Ca2+] and that K+ ions have a direct inhibitory effect on this process. Lipid scrambling in resealed ghosts occurs in the absence of cell shrinkage
and microvesicle formation, processes that are generally attributed to Ca2+-induced lipid scrambling in intact erythrocytes. Thus, opening of Ca2+-sensitive K+ channels causes loss of intracellular K+ that results in reduced intrinsic inhibitory effect of these ions on scramblase activity.
Received 11 September 2008; received after revision 17 October 2008; accepted 27 October 2008 相似文献
11.
It has long been thought that astrocytes, like other glial cells, simply provide a support mechanism for neuronal function in the healthy and inflamed central nervous system (CNS). However, recent evidence suggests that astrocytes play an active and dual role in CNS inflammatory diseases such as multiple sclerosis (MS). Astrocytes not only have the ability to enhance immune responses and inhibit myelin repair, but they can also be protective and limit CNS inflammation while supporting oligodendrocyte and axonal regeneration. The particular impact of these cells on the pathogenesis and repair of an inflammatory demyelinating process is dependent upon a number of factors, including the stage of the disease, the type and microenvironment of the lesion, and the interactions with other cell types and factors that influence their activation. In this review, we summarize recent data supporting the idea that astrocytes play a complex role in the regulation of CNS autoimmunity. 相似文献
12.
Metastasis: cell-autonomous mechanisms versus contributions by the tumor microenvironment 总被引:12,自引:0,他引:12
The fatality of cancer predominantly results from the dissemination of primary tumor cells to distant sites and the subsequent
formation of metastases. During tumor progression, some of the primary tumor cells as well as the tumor microenvironment undergo
characteristic molecular changes, which are essential for the metastatic dissemination of tumor cells. In this review, we
will discuss recent insights into pro-metastatic events occurring in tumor cells themselves and in the tumor stroma. Tumor
cell-intrinsic alterations include the loss of cell polarity and alterations in cell-cell and cell-matrix adhesion as well
as deregulated receptor kinase signaling, which together support detachment, migration and invasion of tumor cells. On the
other hand, the tumor stroma, including endothelial cells, fibroblasts and cells of the immune system, is engaged in an active
molecular crosstalk within the tumor microenvironment. Subsequent activation of blood vessel and lymph vessel angiogenesis
together with inflammatory and immune-suppressive responses further promotes cancer cell migration and invasion, as well as
initiation of the metastatic process.
Received 4 July 2005; received after revision 3 November 2005; accepted 14 November 2005 相似文献
13.
14.
B. C. Yoo S-H. Hong J-L. Ku Y-H. Kim Y-K. Shin S-G. Jang I-J. Kim S-Y. Jeong J-G. Park 《Cellular and molecular life sciences : CMLS》2009,66(2):350-364
Comparative analysis of proteomes using 5-fluorouracil (5-FU)-resistant human colon cancer cell line revealed that decreased
galectin-3 expression was significantly associated with retarded proliferation. However, in the presence of 5-FU proliferation
rate of cells with suppressed galectin-3 expression did not differ from that of cells with normal galectin-3 expression, even
galectin-3 suppression augmented apoptosis. Mechanism by which galectin-3 regulates cancer cell proliferation has been identified
in immunoprecipitates of the anti-galectin-3 antibody. Heterogeneous nuclear ribonucleoprotein Q (hnRNP Q) was identified
as a protein interacting with galectin-3. Interestingly, while galectin-3 protein was not affected by the hnRNP Q level, its
suppression was accompanied by a decrease in hnRNP Q expression. The present study demonstrates that galectin-3 stabilizes
hnRNP Q via complex formation, and reduction in the hnRNP Q level leads to slow proliferation and less susceptibility to 5-FU.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users.
B.C.Yoo; S-H.Hong; These two authors contributed equally to this work.
Received 10 September 2008; received after revision 19 October 2008; accepted 07 November 2008 相似文献
15.
C. Akgul 《Cellular and molecular life sciences : CMLS》2009,66(8):1326-1336
Resistance to apoptosis is a common challenge in human malignancies contributing to both progress of cancer and resistance
to conventional therapeutics. Abnormalities in a variety of cell intrinsic and extrinsic molecular mechanisms cooperatively
promote tumor formation. Therapeutic approaches that specifically target components of these molecular mechanisms are getting
widespread attention. Mcl-1 is a highly expressed pro-survival protein in human malignancies and its cellular expression is
tightly regulated via multiple mechanisms. Mcl-1 differs from other members of the Bcl-2 family in having a very short half-life. So inhibition
of its expression and/or neutralization of its anti-apoptotic function will rapidly make Mcl-1-dependent cells more susceptible
to apoptosis and provide an opportunity to combat several types of cancers. This review summarizes the current knowledge on
the regulation of Mcl-1 expression and discusses the alternative approaches targeting Mcl-1 in human cancer cells whose survivals
mainly depend on Mcl-1.
Received 6 October 2008; received after revision 21 October 2008; accepted 10 November 2008 相似文献
16.
Monocytes and their pathophysiological role in Crohn’s disease 总被引:1,自引:1,他引:0
Zhou L Braat H Faber KN Dijkstra G Peppelenbosch MP 《Cellular and molecular life sciences : CMLS》2009,66(2):192-202
Our immune system shows a stringent dichotomy, on the one hand displaying tolerance towards commensal bacteria, but on the
other hand vigorously combating pathogens. Under normal conditions the balance between flora tolerance and active immunity
is maintained via a plethora of dynamic feedback mechanisms. If, however, the balancing act goes faulty, an inappropriate
immune reaction towards an otherwise harmless intestinal flora causes disease, Crohn’s disease for example. Recent developments
in the immunology and genetics of mucosal diseases suggest that monocytes and their derivative cells play an important role
in the pathophysiology of Crohn’s disease. In our review, we summarize the recent studies to discuss the dual function of
monocytes - on the one hand the impaired monocyte function initiating Crohn’s disease, and on the other hand the overactivation
of monocytes and adaptive immunity maintaining the disease. With a view to developing new therapies, both aspects of monocyte
functions need to be taken into account.
Received 1 June 2008; received after revision 24 July 2008; accepted 13 August 2008 相似文献
17.
Until recently, the expression and primary function of the cell surface receptor CD40 and its ligand CD154 were considered
restricted to B and T lymphocytes, and their interactions required for the thymus-dependent humoral response. However, current
work from several groups challenges this view of the CD40/CD154 dyad as a mere mediator of lymphocyte communication. A variety
of non-lymphocytic cell types express both receptor and ligand, including hematopoetic and non-hematopoetic cells, such as
monocytes, basophils, eosinophils, dendritic cells, fibroblasts, smooth muscle, and endothelial cells. Accordingly, ligation
of CD40 mediates a broad variety of immune and inflammatory responses, such as the expression of adhesion molecules, cytokines,
matrix-degrading enzymes, prothrombotic activities, and apoptotic mediators. Consequently, CD40 signaling has been associated
with pathogenic processes of chronic inflammatory diseases, such as autoimmune diseases, neurodegenerative disorders, graft-versus-host
disease, cancer, and atherosclerosis. This review focuses on the synthesis and structure of CD40 and outlines CD154/CD40 signaling
pathways, and emphasizes the previously unexpected importance of the CD40/CD154 receptor/ligand dyad in a spectrum of immunoregulatory
processes and prevalent human diseases.
Received 10 January 2000; revised 16 June 2000; accepted 5 July 2000
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ID="*" Corresponding author. 相似文献
18.
Multi-layered regulation of intestinal antimicrobial defense 总被引:1,自引:0,他引:1
Mukherjee S Vaishnava S Hooper LV 《Cellular and molecular life sciences : CMLS》2008,65(19):3019-3027
19.
Di Felice V David S Cappello F Farina F Zummo G 《Cellular and molecular life sciences : CMLS》2005,62(1):4-9
Heat shock protein 60 (HSP60) plays an important role in the protein folding of prokaryotic and eukaryotic cells. Most of the papers published on chlamydial HSP60 concern its role in immune response during infection. In the last decade, exposure to Chlamydia trachomatis has been consistently associated with the development of cervical and ovarian cancer. Moreover, it has been suggested that chlamydial HSP60 may have an anti-apoptotic effect during persistent infection. We hypothesize that the accumulation of exogenous chlamydial HSP60 in the cytoplasm of actively replicating eukaryotic cells may interfere with the regulation of the apoptotic pathway. The concomitant expression of viral oncoproteins and/or the presence of mutations may lead to the ability to survive apoptotic stimuli, loss of replicative senescence, uncontrolled proliferation and, finally neoplastic transformation.Received 15 August 2004; received after revision 1 October 2004; accepted 7 October 2004 相似文献
20.
Mechanisms of HIV-mediated CD4+ T cell loss leading to immunodeficiency are amongst the most extensively studied yet unanswered
questions in HIV biology. The level of CD4+ T cell depletion in HIV infected patients far exceeds the number of infected T
cells, suggesting an indirect mechanism of HIV pathogenesis termed bystander cell death. Evidence is accumulating that the
HIV envelope glycoprotein (Env) is a major determinant of HIV pathogenesis and plays a critical role in bystander cell death.
The complex structure and function of HIV Env makes the determination of the mechanism of Envmediated apoptosis more complex
than previously thought. This review will examine the complex relationship between HIV Env phenotype, coreceptor expression
and immune activation in determining HIV pathogenesis. We review data here corresponding to the role of HIV Env hemifusion
activity in HIV pathogenesis and how it interplays with other AIDS associated factors such as chemokine receptor expression
and immune activation.
Received 21 March 2008; received after revision 29 April 2008; accepted 30 April 2008 相似文献