Factor Crosstalk Research Articles

Nitric oxide/platelet activating factor cross-talk in mesangial cells modulates the interaction with leukocytes

Platelet activating factor (PAF) and nitric oxide (NO) exert opposite effects on adherence and activation of circulating leukocytes to endothelium. Several studies have implicated the production of PAF and NO by mesangial cells in the regulation of glomerular filtration, permeability and inflammation. However, the reciprocal interaction between PAF and NO in mesangial cells and their role in leukocyte adhesion has not been investigated. We evaluated whether blockade of constitutive production of NO by two different NO synthase (NOS) inhibitors (L-NAME and L-NMMA) could modulate PAF synthesis, and conversely whether exogenous PAF could influence the production of NO by mesangial cells. We evaluated whether modulation of PAF synthesis by NOS inhibitors could affect leukocyte adhesion to mesangial cells. The effect of PAF-receptor antagonist WEB2170, of anti-beta(2) integrins and intracellular adhesion molecule-1 (ICAM-1) blocking antibodies and of soluble Sialyl-Lewis-a also was evaluated. Blockade of NO synthesis by NOS inhibitors induced a spontaneous synthesis of PAF that was conversely inhibited by NO generation. On the other hand, PAF inhibited both the basal and l-arginine induced synthesis of NO by mesangial cells. Moreover, NOS inhibition promoted the adhesion of polymorphonuclear cells and monocytes to mesangial cells by a mechanism dependent on the synthesis of PAF and on the interaction of beta(2) integrins and ICAM-1. These data indicate that PAF and NO exhibit a bi-directional effect on their respective synthesis in human mesangial cells, and suggest that their reciprocal regulation may be relevant for leukocyte adhesion to glomerular mesangial cells.

Nitric oxide/platelet activating factor cross-talk in mesangial cells modulates the interaction with leukocytes

Nitric oxide/platelet activating factor cross-talk in mesangial cells modulates the interaction with leukocytes.BackgroundPlatelet activating factor (PAF) and nitric oxide (NO) exert opposite effects on adherence and activation of circulating leukocytes to endothelium. Several studies have implicated the production of PAF and NO by mesangial cells in the regulation of glomerular filtration, permeability and inflammation. However, the reciprocal interaction between PAF and NO in mesangial cells and their role in leukocyte adhesion has not been investigated.MethodsWe evaluated whether blockade of constitutive production of NO by two different NO synthase (NOS) inhibitors (L-NAME and L-NMMA) could modulate PAF synthesis, and conversely whether exogenous PAF could influence the production of NO by mesangial cells. We evaluated whether modulation of PAF synthesis by NOS inhibitors could affect leukocyte adhesion to mesangial cells. The effect of PAF-receptor antagonist WEB2170, of anti-β2 integrins and intracellular adhesion molecule-1 (ICAM-1) blocking antibodies and of soluble Sialyl-Lewis-a also was evaluated.ResultsBlockade of NO synthesis by NOS inhibitors induced a spontaneous synthesis of PAF that was conversely inhibited by NO generation. On the other hand, PAF inhibited both the basal and L-arginine induced synthesis of NO by mesangial cells. Moreover, NOS inhibition promoted the adhesion of polymorphonuclear cells and monocytes to mesangial cells by a mechanism dependent on the synthesis of PAF and on the interaction of β2 integrins and ICAM-1.ConclusionsThese data indicate that PAF and NO exhibit a bi-directional effect on their respective synthesis in human mesangial cells, and suggest that their reciprocal regulation may be relevant for leukocyte adhesion to glomerular mesangial cells. Nitric oxide/platelet activating factor cross-talk in mesangial cells modulates the interaction with leukocytes. Platelet activating factor (PAF) and nitric oxide (NO) exert opposite effects on adherence and activation of circulating leukocytes to endothelium. Several studies have implicated the production of PAF and NO by mesangial cells in the regulation of glomerular filtration, permeability and inflammation. However, the reciprocal interaction between PAF and NO in mesangial cells and their role in leukocyte adhesion has not been investigated. We evaluated whether blockade of constitutive production of NO by two different NO synthase (NOS) inhibitors (L-NAME and L-NMMA) could modulate PAF synthesis, and conversely whether exogenous PAF could influence the production of NO by mesangial cells. We evaluated whether modulation of PAF synthesis by NOS inhibitors could affect leukocyte adhesion to mesangial cells. The effect of PAF-receptor antagonist WEB2170, of anti-β2 integrins and intracellular adhesion molecule-1 (ICAM-1) blocking antibodies and of soluble Sialyl-Lewis-a also was evaluated. Blockade of NO synthesis by NOS inhibitors induced a spontaneous synthesis of PAF that was conversely inhibited by NO generation. On the other hand, PAF inhibited both the basal and L-arginine induced synthesis of NO by mesangial cells. Moreover, NOS inhibition promoted the adhesion of polymorphonuclear cells and monocytes to mesangial cells by a mechanism dependent on the synthesis of PAF and on the interaction of β2 integrins and ICAM-1. These data indicate that PAF and NO exhibit a bi-directional effect on their respective synthesis in human mesangial cells, and suggest that their reciprocal regulation may be relevant for leukocyte adhesion to glomerular mesangial cells.

Oestrogen and growth factor cross-talk and endocrine insensitivity and acquired resistance in breast cancer.

Oestrogen and growth factor cross-talk and endocrine insensitivity and acquired resistance in breast cancer

Involvement of steroid hormone and growth factor cross-talk in endocrine response in breast cancer.

Multiple lines of evidence implicate steroid hormone and growth factor cross-talk as a modulator of endocrine response in breast cancer and that aberrations in growth factor signaling pathways are a common element in the endocrine resistant phenotype. Delineation of these relationships is thus an important diagnostic goal in cancer research, while the targeting of aberrant growth factor signaling holds the promise of improving therapeutic response rates.

Transcriptional cross-talk, the second mode of steroid hormone receptor action.

Physiological and therapeutic activities of glucocorticoids and other steroid hormones are mediated by the family of steroid hormone receptors. In addition to the classical mode of receptor action which involves binding as a dimer to regulatory sequences in target gene promoters and subsequent activation of transcription, a second mode of action is based predominantly on protein-protein interactions. As the paradigm of this so-called transcriptional cross-talk, the glucocorticoid receptor (GR) and the AP-1 transcription factor interact on target gene promoters which contain only a binding site for either one of the two transcription factors. Most frequently negative interference of both factors with each other's activity has been observed, for example, when AP-1 is composed of c-Fos and c-Jun; however, synergism is also possible under cell-specific conditions and when AP-1 is a homodimer of c-Jun. Since the detection of the GR/AP-1 cross-talk numerous other examples of transcription factor interactions have been described. Many members of the nuclear hormone receptor superfamily, including class II receptors, have been shown to participate in such cross-talk. Moreover, the transcription factor families of NF-kappaB/Rel as well as Stat, Oct, and C/EBP are engaged in cross-talk with steroid receptors. Despite the identification of a multitude of target genes which appear to be regulated by this type of transcription factor interaction, the exact molecular mechanism of the cross-talk has not yet been elucidated. This review discusses the current models to explain the molecular events of transcription factor cross-talk. Concepts are emphasized which suggest that the classical and the cross-talk mode of steroid receptor action can be triggered separately by the choice of specific ligands. A final section summarizes the partially contradictory data which assign a certain type of receptor action to a biological response particularly in the immune system.

Oestrogen/growth factor cross-talk in breast carcinoma: a specific target for novel antioestrogens.

Breast cancer cells express receptors for and are sensitive to a variety of steroids, polypeptide hormones and growth factors; the blocking of and/or the interference with their biochemical pathways could represent a new approach to breast tumour therapy. Antioestrogens achieve such a goal by competing with oestradiol for binding to the oestrogen receptors through which intracellular effects of the hormone are mediated. Tamoxifen has undergone the most extensive clinical evaluations and represents the treatment of choice for the endocrine management of breast cancer. Nevertheless, it is well known that tamoxifen retains agonist activity both in vitro and in vivo. To circumvent this disadvantage, new molecules with steroid-like structure, represented by ICI 164,384 and ICI 182,780, have been synthesized. In this review, Alessandra de Cupis and Roberto Favoni review data about the cross-talk between the two major families of breast cancer growth regulator: oestrogens and growth factors, focusing on the use of nonsteroidal antioestrogens and the new generation of steroidal antioestrogens as possible specifically targeted inhibitors of breast tumour proliferation.

Peptide growth factor cross-talk with the estrogen receptor requires the A/B domain and occurs independently of protein kinase C or estradiol.

Modulation of steroid receptor-dependent transcription by extra- cellular ligands represents a novel mechanism of steroid receptor regulation. We have assessed the effects of epidermal growth factor (EGF), transforming growth factor-alpha (TGF alpha), and insulin-like growth factor I (IGF-I) on transcription from consensus estrogen response elements (ERE) in estrogen receptor (ER)-positive BG-1 human ovarian adenocarcinoma calls. EGF, TGF alpha, IGF-I, and estradiol (E2) enhanced transcription in a dose-dependent manner using either a strong or a minimal promoter, and ICI 164,384, a specific ER antagonist, inhibited these responses. Combinations of E2 with TGF alpha or IGF-I induced synergistic activation of transcription from an ERE, whereas as additive response was observed with combinations of IGF-I and TGF alpha of EGF. Tetradecanoyl 12-phorbol 13-acetate (TPA), a protein kinase C (PKC) activator, stimulated ERE-mediated transcription, and this effect was inhibited by ICI 164,384. Bisindolylmaleimide, a relatively specific inhibitor of PKC, completely antagonized TPA-induced transcription, but did not affect the response to TGF alpha, IGF-I, or E2. The combination of TPA with E2 in transcriptional synergism was inhibited by ICI 164,384; conversely, the combination of TPA with either TGF alpha of IGF-I elicited a response only equal to the maximal TPA response. Thus, peptide growth factors elicit ER-dependent transcription independently of PFC; however, there may be a common mechanistic component, as saturation of response was observed. Finally, activation of ERE-dependent transcription in Chinese hamster ovary cells by IGF-I was observed in the presence of a mutant receptor that lacks estrogen-binding activity. The effect of both IGF-I and E2 were dependent on the ability of the ER to bind to DNA. IGF-I elicited only weak transcriptional activation in the presence of a deletion mutant that lacked the entire A/B domain; however, synergism between IGF-I and E2 was observed with this mutant. Therefore, ligand-independent activation of ER-dependent transcription by IGF-I is predominantly mediated through activation function I by a mechanism distinct from that of E2.

Peptide growth factor cross-talk with the estrogen receptor requires the A/B domain and occurs independently of protein kinase C or estradiol

Peptide growth factor cross-talk with the estrogen receptor requires the A/B domain and occurs independently of protein kinase C or estradiol

Smart optical receiver with automatic decision threshold setting and retiming phase alignment

The requirements for a smart optical receiver are discussed, and a design architecture suitable for introducing ICs based on automatic decision threshold setting and retiming phase alignment using digital/analog signal processing feedback is proposed. With the proposed architecture, the decision threshold level and the retiming clock phase of received data in the decision circuit are automatically adjusted to the optimum position. This obviates the need for decision threshold level and retiming clock phase adjustments in production testing, and it reduces the power penalty (receiver sensitivity degradation) on the received optical waveform variation. The power penalty caused by temperature and supply-voltage variations and aging in installation is also reduced. The performance of the proposed architecture is estimated; the power penalty as compared with the manual optimum adjustment is less than 0.4 dB, and the robustness to avalanche photodiode multiplication factor variations and crosstalk are improved. >

66. Significance of “infarcts” on magnetic resonance imaging (MRI) scans in demented subjects

Activation of the aryl hydrocarbon receptor (AhR1) by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) elicits severe immunosuppression accompanied by thymic atrophy. Previous evidence suggests that TCDD targets both thymocytes and thymic epithelial cells. The AhR induces cell-specific changes in gene transcription via binding to the dioxin response element DRE; however, the underlying specificity-mechanisms, in particular with regard to the role of promoter element context, and possible transcription factor crosstalk remain poorly understood. Global gene expression in the cortical thymic epithelial cell line ET at 2, 4, and 6 h following 5 nM TCDD exposure resulted in differential regulation of 201 genes. JASPAR and TRANSFAC mapped the statistically over-represented promoter elements in the regulated genes to specific transcription factor binding sites, suggesting a regulatory role in AhR signaling. Over-represented elements included the xenobiotic response element XRE, NFκB-Rel, HRE, PPARγ, GR, PAX-4 and estrogen receptor binding sites. Co-treatment experiments with TCDD and CoCl2, to induce hypoxia, or TCDD and 17-β-estradiol (E2) indicated crosstalk between AhR and Hif or ER, in agreement with other experimental models. The computational identification of TFBS and the demonstration of interaction confirm their interactions with AhR signaling and suggest that the other over-represented elements may also be important in the immunosuppressive effects elicited by TCDD. In conclusion, we demonstrated the importance of promoter element cooperation in the shaping of a cell-specific AhR response. Our findings regarding the transcriptional changes in cortical epithelial cells are congruent with the well-known thymotoxic TCDD-phenotype, and useful in new hypothesis generation of the role of cortical TECs in TCDD toxicity.