Activation via the CD3 and CD16 pathway mediates interleukin-2-dependent autocrine proliferation of granular lymphocytes in patients with granular lymphocyte proliferative disorders. is an eagle-i resource of type Journal article at Oregon Health & Science University.

Down syndrome (DS; trisomy 21) is the most common genetic cause of mental retardation, affecting about one in every 800 individuals. About 60% of the genes on human chromosome 21 are present on mouse chromosome 16 and mouse trisomy 16 (Ts16) has been studied as a potential model for DS. Cultured hippocampal neurons from embryonic Ts16 mice undergo accelerated death by apoptosis in vitro compared with neurons from Euploid littermates. The purpose of this study was to determine the molecular mechanism underlying this accelerated death. Brain-derived Neurotrophic Factor (BDNF), acting through its receptor, trkB, is a well-described autocrine survival factor for hippocampal neurons. BDNF binding to trkB initiates receptor dimerization, autophosphorylation, and activation of several signaling pathways, including AKT and ERK, two signal transduction molecules whose activation by phosphorylation promotes cell survival. To test whether BDNF promoted autocrine survival in Euploid and Ts16 neuronal ...

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Cutaneous squamous tumors rely on autocrine/paracrine loops for proper fitness. Targeting this Achilles heel is therefore considered a potential avenue for patient treatment. However, the mechanisms that engage and sustain such programs during tumor ontogeny are poorly understood. Here, we show that two Rho/Rac activators, the exchange factors Vav2 and Vav3, control the expression of an epithelial autocrine/paracrine program that regulates keratinocyte survival and proliferation as well as the creation of an inflammatory microenvironment. Vav proteins are also critically involved in some of the subsequent autocrine signaling loops activated in keratinocytes. The genetic inactivation of both Vav proteins reduces tumor multiplicity without hampering skin homeostasis, thus suggesting that pan-specific Vav therapies may be useful in skin tumor prevention and treatment. The dorsal skin of WT and DKO mice (Vav2-/-;Vav3-/-) were treated with either one or four applications of phorbol ester 12-O

A large number of cells in the airways, such as eosinophils, mast cells, lymphocytes, neutrophils and ASM cells, contribute to the pathogenesis of inflammatory airway diseases. Here we specifically discuss potential anti-inflammatory interventions that target ASM-driven inflammation.. As mentioned earlier, ASM cells are potential targets for glucocorticosteroid therapy. Other workers and ourselves have recently demonstrated that the expression and secretion of pro-inflammatory cytokines and chemokines by ASM cells in vitro can be inhibited by glucocorticosteroid treatment [11,12,17,25,26,32,36,40]. COX-2 induction and the resulting production of arachidonic acid metabo-lites could similarly be inhibited by treatment with dexa-methasone [13,51]. Suppression of the COX-2 pathway, on the contrary, may result in deleterious consequences considering the bronchoprotective properties of PGE2 in asthmatic airways.. Mechanistically, it has been proposed that glucocorticoid receptors interact with ...

In this study, we showed that exogenously supplied VEGF and TGF-β rapidly increased Cx43 expression in cultured neonatal rat ventricular myocytes in a manner similar to the effects induced by brief intervals of linear pulsatile stretch. We also showed that specific antibodies against either VEGF or TGF-β blocked stretch-induced upregulation of Cx43 expression. Stretch-conditioned medium contained increased levels of VEGF and was able to stimulate Cx43 expression in cells not subjected to stretch. Anti-VEGF antibody blocked the effects of exogenous TGF-β on Cx43 expression but anti-TGF-β antibody did not block the VEGF effect. Thus, we confirmed original observations by Seko et al3 that pulsatile stretch stimulates secretion of VEGF, mediated at least in part by TGF-β, and we now provide evidence that directly implicates these pathways in stretch-mediated upregulation of Cx43.. It is likely that pulsatile stretch causes secretion of multiple mediators from cardiac myocytes and nonmyocytic ...

My research program focuses on the regulation of cholangiocyte proliferation/damage during cholangiopathies. My studies have demonstrated the key role of a number of factors such as vascular and nerve factors, melatonin, secretin, biogenic amines and sex hormones (expressed and secreted by cholangiocytes) in the regulation of biliary growth/damage by autocrine/paracrine mechanisms. Proliferating cholangiocytes display a neuroendocrine phenotype and secrete and respond to a number of hormones, neuropeptides and neurotransmitters in autocrine and paracrine signaling mechanisms. My research interests also include determining the interactions that occur between cholangiocytes and other cell types (such as hepatocytes, hepatic stellate cells, and vascular endothelial cells) in the biliary microenvironment during both cholestasis and cholangiocarcinogenesis. My program evaluates the various signaling mechanisms regulating the balance between biliary growth/damage. I have expertise in the areas of ...

|jats:p|Resident fibroblasts at sites of infection, chronic inflammation, or cancer undergo phenotypic and functional changes to support leukocyte migration and, in some cases, aggregation into tertiary lymphoid structures (TLS). The molecular programming that shapes these changes and the functional requirements of this population in TLS development are unclear. Here, we demonstrate that external triggers at mucosal sites are able to induce the progressive differentiation of a population of podoplanin (pdpn)-positive stromal cells into a network of immunofibroblasts that are able to support the earliest phases of TLS establishment. This program of events, that precedes lymphocyte infiltration in the tissue, is mediated by paracrine and autocrine signals mainly regulated by IL13. This initial fibroblast network is expanded and stabilized, once lymphocytes are recruited, by the local production of the cytokines IL22 and lymphotoxin. Interfering with this regulated program of events or depleting the

Chronic inflammation and allergy involve the activation of tissue-resident cells and, later on, the invasion of effector cells. We have previously shown that the loss of phosphoinositide 3-kinase (PI3K) γ impairs chemokine-dependent migration of neutrophils and macrophages both in vitro and in vivo. On the other hand, PI3Kγ is not required either during phagocytic processes or in the activation of bactericidal activities like granule secretion and particle-mediated respiratory burst in neutrophils. Tissue mast cells are key regulators in allergy and inflammation and release histamine upon clustering of their IgE receptors. We have demonstrated that murine mast cell responses are exacerbated in vitro and in vivo by autocrine signals, and require functional PI3Kγ. Adenosine, acting through the A3 adenosine receptor, as well as other agonists of Gαi-coupled receptors, transiently increased PtdIns(3,4,5)P3 exclusively via PI3Kγ. PI3Kγ-derived PtdIns(3,4,5)P3 was instrumental for initiation of ...

Fingerprint Dive into the research topics of Autocrine-paracrine inhibition of growth hormone and prolactin production by GH,sub,3,/sub, cell-conditioned medium. Together they form a unique fingerprint. ...

Amphiregulin (AR) is a newly discovered glycosylated, 84-amino acid residue polypeptide growth regulator which has sequence homology to the EGF family of proteins. To obtain immunological reagents to study the biological role of AR, two synthetic peptides containing sequences corresponding to distinct regions of AR were used to generate polyclonal antibodies in rabbits. One preparation of antipeptide antibodies directed against residues 26-44 of AR (AR-Ab2) was most effective in the detection of native AR, whereas another preparation of antibodies against residues 8-26 (AR-Ab1) was found to be most efficacious in the detection of AR in formalin-fixed and paraffin-embedded tissues. The growth of a colon carcinoma cell line, Geo, which proliferates autonomously under serum-free conditions, was stimulated by the exogenous addition of AR or EGF. Half-maximal stimulation of this growth was observed at 40 and 200 pM of EGF and AR, respectively. A mAb to the extracellular domain of the EGF receptor ...

This allows a competent direct communication between -cells as well as the intra-islet capillaries, ensuring an instant response to increases in blood sugar levels by secreting insulin [180,181]. advancement of T2DM. IGF-1 and Insulin signaling pathways play critical tasks in maintaining the differentiated phenotype of -cells. The autocrine actions of secreted insulin on -cells is controversial still; function by us while others offers shown positive and negative activities by insulin on -cells. We discuss results that support the idea of an autocrine actions of secreted insulin on -cells. The hypothesis of whether, through the advancement of T2DM, secreted insulin primarily functions as a good friend and plays a part in -cell payment and, at a stage later, turns into a foe and plays a part in -cell decompensation will be discussed. gene in mice led to lack of -cell phenotype due to impaired manifestation of insulin as well as the blood sugar transporter, Glut2; these mice created T2DM with age ...

Autocrine signaling is a form of cell signaling in which a cell secretes a hormone or chemical messenger (called the autocrine agent) that binds to autocrine receptors on that same cell, leading to changes in the cell. This can be contrasted with paracrine signaling, intracrine signaling, or classical endocrine signaling. An example of an autocrine agent is the cytokine interleukin-1 in monocytes. When interleukin-1 is produced in response to external stimuli, it can bind to cell-surface receptors on the same cell that produced it.[citation needed] Another example occurs in activated T cell lymphocytes, i.e., when a T cell is induced to mature by binding to a peptide:MHC complex on a professional antigen-presenting cell and by the B7:CD28 costimulatory signal. Upon activation, low-affinity IL-2 receptors are replaced by high-affinity IL-2 receptors consisting of α, β, and γ chains. The cell then releases IL-2, which binds to its own new IL-2 receptors, causing self-stimulation and ...

Purified anti-human/mouse IL-21 Antibody - Interleukin 21 (IL-21) is a potent immunomodulatory cytokine mainly produced by NKT and CD4+ T-cells, particularly the inflammatory Th17 subset and has pleiotropic effects on both innate and adaptive immune responses.  These actions include positive effects such as enhancing proliferation of NK cells and cytotoxic T cells, and inhibitory effects on the antigen-presenting function of dendritic cells.  It can also be proapoptotic for B cells and NK cells.  Recent studies have shown that IL-21 is also an autocrine cytokine that potently induces T(H)17 differentiation and suppresses Foxp3 expression, and serves as a target for treating inflammatory diseases..

Purified anti-human/mouse IL-21 Antibody - Interleukin 21 (IL-21) is a potent immunomodulatory cytokine mainly produced by NKT and CD4+ T-cells, particularly the inflammatory Th17 subset and has pleiotropic effects on both innate and adaptive immune responses.  These actions include positive effects such as enhancing proliferation of NK cells and cytotoxic T cells, and inhibitory effects on the antigen-presenting function of dendritic cells.  It can also be proapoptotic for B cells and NK cells.  Recent studies have shown that IL-21 is also an autocrine cytokine that potently induces T(H)17 differentiation and suppresses Foxp3 expression, and serves as a target for treating inflammatory diseases..

Lytic CD8+ T cells at the psoriasis plaques epidermis secrete IL‐17, IL‐21 and IL‐22 and depends on autocrine TNFalpha production. IL‐17‐producing CD4+ T ...

Takaoka et al. have presented persuasive evidence that in MEFs the IFN-γ response is substantially augmented through autocrine IFN-α/β and that cross-recruitment and phosphorylation of the IFNAR1 subunit of the IFN-α/β receptor occurs in response to IFN-γ in these cells (24). We have been unable to obtain evidence for or against recruitment or phosphorylation of IFNAR1 in response to IFN-γ in the HT1080-based human cell systems used here (H. Isharc and I. M. Kerr, unpublished data). In a potentially analogous but inverse situation, cross-phosphorylation of the IFNGR1 subunit of the IFN-γ receptor in response to activation of erythropoietin/gp130 receptor chimeras in HT1080-based cell lines is observed. Importantly, however, such receptor cross-phosphorylation plays no part in the IFN-γ-like response observed (23), a result which emphasizes that even if IFNAR1 were recruited and phosphorylated in response to IFN-γ, proof of necessity of this for the IFN-γ antiviral response would ...

Despite the considerable improvements in our knowledge of AML biology in recent years, the treatment of this disease remains a challenge for clinicians. Major efforts have been made to develop new compounds that target the preferentially activated signaling pathways implicated in AML cell proliferation and survival. The PI3K/Akt/mTOR axis represents a promising therapeutic target in several cancers, as many components of these signaling pathways are frequently deregulated in tumor cells. We recently showed that a constitutive activation of PI3K is detected in ∼50% of primary AML samples at diagnosis(8), mostly due to an autocrine stimulation of the IGF-1 receptor (9). Accordingly, either the blockade of this IGF-1 autocrine production or the specific inhibition of PI3K p110δ activity leads to a strong decrease of AML cell proliferation (4, 5, 9). The constitutive activation of the mTORC1 pathway is detectable in virtually almost all AML patient samples, which emphasized the potential of using ...

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For several years there has been considerable interest in stimulating angiogenesis by a variety of growth factors, including the family of fibroblast growth factors (FGF). FGF-5 is a protooncogene known to stimulate cell growth and proliferation in multiple cell types, including cancer.1 The cardiac myocyte can also produce different isoforms of FGFs, eg, it has been shown that the expression of basic FGF increases in hibernating myocardium,2 which was the disease state of interest in the current study published in Circulation Research.3 The most commonly cited effect of FGF-5 in the heart is to promote angiogenesis. Several studies have shown that gene transfer of FGF-5 in the heart increases vessel formation and regional blood flow.4-6 This effect is mediated by a production of FGF-5 by the cardiac myocytes, followed by its release in the extracellular space. In addition, FGF-5 can function as an autocrine/paracrine mechanism of cardiac cell growth and as a cytoprotective mechanism against ...

Lipoxygenases (EC 1.13.11.-) are a family of (non-heme), iron-containing enzymes most of which catalyze the dioxygenation of polyunsaturated fatty acids in lipids containing a cis,cis-1,4- pentadiene into cell signaling agents that serve diverse roles as autocrine signals that regulate the function of their parent cells, paracrine signals that regulate the function of nearby cells, and endocrine signals that regulate the function of distant cells. The lipoxygenases are related to each other based upon their similar genetic structure and dioxygenation activity. However, one lipoxygenase, ALOXE3, while having a lipoxygenase genetic structure, possesses relatively little dioxygenation activity; rather its primary activity appears to be as an isomerase that catalyzes the conversion of hydroperoxy unsaturated fatty acids to their 1,5-epoxide, hydroxyl derivatives. Lipoxygenases are found in eukaryotes (plants, fungi, animals, protists); while the third domain of terrestrial life, the archaea, ...

Phlogistic reactions, whether of extraocular or intraocular origin, tend to be down regulated by the avascular, and hence immune privileged, cornea. And this feature is recognised as being essential for a favourable graft prognosis. In situ, corneal tissue is protected from potential inflammatory stimulants, such as endotoxins, by the epithelial and vascular barriers; but in vitro, the situation is different. Under these conditions, contamination of culture media with endotoxins could have untoward effects; these may be manifested either directly, by overt changes in cell morphology, and/or by a more discreet influence on the tissues immunological status, the consequences of which may be realised only after transplantation, by a compromised graft performance.. In the current study, we monitored the media of organ cultured corneas for a number of cytokine mediators of the inflammatory response, both before and after spiking with endotoxin; these data were then compared with those pertaining to ...

article{99c2b32e-f9cf-4afb-8052-6d71d776ad00, abstract = {The first lineage commitment step of hematopoietic stem cells (HSC) results in separation into distinct lymphoid and myeloid differentiation pathways, reflected in the generation of common lymphoid and myeloid progenitors (CLP and CMP, respectively). In this report we present the first evidence for a nonredundant regulator of this process, in that adult mice deficient in expression of the flt3 ligand (FL) have severely (10-fold) reduced levels of the CLP, accompanied by reductions in the earliest identifiable B and T cell progenitors. In contrast, CMP and HSC are unaffected in FL-deficient mice. Noteworthy, CLP express high levels of both the flt3 receptor and ligand, indicating a potential autocrine role of FL in regulation of the earliest lymphoid commitment step from HSC.}, author = {Sitnicka Quinn, Ewa and Bryder, David and Theilgaard-Mönch, Kim and Buza-Vidas, Natalija and Adolfsson, Jörgen and Jacobsen, Sten Eirik W}, issn = ...

Our hypothesis is based on several lines of evidence. First, the effects of cAMP and DA on both 4xCRE (Figs. 3a,b, 5) and c-fos and BDNF mRNA expression (Fig. 6) are blocked by NMDAR antagonists. Second, two structurally distinct inhibitors of neuronal EAA uptake, TBOA (Fig. 7) and trans-PDC (supplemental Fig. S3, available at www.jneurosci.org as supplemental material), potentiated the stimulation of gene transcription by cAMP. Third, the aspartate+glutamate-, but not the glutamate-only-, scavenging system abolished stimulation of CREB-dependent gene transcription by forskolin (Fig. 8); the aspartate-scavenging enzyme, GOT, degrades l- but not d-aspartate demonstrating that l-aspartate is the active extracellular EAA in this signaling pathway. Finally, forskolin was found to induce release of aspartate but not glutamate (Fig. 9). Together, these results lead to the conclusion that cAMP-induced release of aspartate and the resulting activation of NR2B-containing NMDARs mediate the effects of ...

Looking for online definition of autocrine in the Medical Dictionary? autocrine explanation free. What is autocrine? Meaning of autocrine medical term. What does autocrine mean?

1. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61:69-90 2. Bosetti C, Turati F, La Vecchia C. Hepatocellular carcinoma epidemiology. Best Pract Res Clin Gastroenterol. 2014;28:753-770 3. Li S, Sun R, Chen Y, Wei H, Tian Z. TLR2 limits development of hepatocellular carcinoma by reducing IL18-mediated immunosuppression. Cancer Res. 2015;75:986-995 4. Naugler WE, Sakurai T, Kim S, Maeda S, Kim K, Elsharkawy AM, Karin M. Gender disparity in liver cancer due to sex differences in MyD88-dependent IL-6 production. Science. 2007;317:121-124 5. He G, Dhar D, Nakagawa H, Font-Burgada J, Ogata H, Jiang Y, Shalapour S, Seki E, Yost SE, Jepsen K, Frazer KA, Harismendy O, Hatziapostolou M, Iliopoulos D, Suetsugu A, Hoffman RM, Tateishi R, Koike K, Karin M. Identification of liver cancer progenitors whose malignant progression depends on autocrine IL-6 signaling. Cell. 2013;155:384-396 6. Gu FM, Li QL, Gao Q, Jiang JH, Zhu K, Huang XY, Pan JF, Yan J, ...

Epithelial branching morphogenesis drives the development of organs such as the lung, salivary gland, kidney and the mammary gland. It involves cell proliferation, cell differentiation and cell migration. An elaborate network of chemical and mechanical signals between the epithelium and the surrounding mesenchymal tissues regulates the formation and growth of branching organs. Surprisingly, when cultured in isolation from mesenchymal tissues, many epithelial tissues retain the ability to exhibit branching morphogenesis even in the absence of proliferation. In this work, we propose a simple, experimentally plausible mechanism that can drive branching morphogenesis in the absence of proliferation and cross-talk with the surrounding mesenchymal tissue. The assumptions of our mathematical model derive from in vitro observations of the behaviour of mammary epithelial cells. These data show that autocrine secretion of the growth factor TGFβ1 inhibits the formation of cell protrusions, leading to ...

The growing knowledge behind the mechanism of autocrine signaling in cancer progression has revealed new approaches for therapeutic treatment. For example, autocrine Wnt signaling could provide a novel target for therapeutic intervention by means of Wnt antagonists or other molecules that interfere with ligand-receptor interactions of the Wnt pathway.[2][3] In addition, VEGF-A production and VEGFR-2 activation on the surface of breast cancer cells indicates the presence of a distinct autocrine signaling loop that enables breast cancer cells to promote their own growth and survival by phosphorylation and activation of VEGFR-2. This autocrine loop is another example of an attractive therapeutic target.[8]. In HER2 overexpressing breast cancers, the HER2-IL-6-STAT3 signaling relationship could be targeted to develop new therapeutic strategies.[6] HER2 kinase inhibitors, such as lapatinib, have also demonstrated clinical efficacy in HER2 overexpressing breast cancers by disrupting a neuregulin-1 ...

Nitric oxide-generating system as an autocrine mechanism in human polymorphonuclear leucocytes.: Recent data [Lopéz-Farré, Riesco, Moliz, Egido, Casado, Hernand

Programmed cell death has a vital role in embryonic development and tissue homeostasis. oxygen varieties (ROS) in tuberculosis illness. Experimental studies have also demonstrated that upregulation of RIPK3 and MLKL detected in alcoholic and drug-induced liver injury suggests that necroptosis is also involved in sterile inflammation. Application of Necrostatin (Nec)-1 or depletion of RIPK3 protects liver cells from these types of injuries [74]. Parasitic diseases like leishmaniasis and malaria generally caused hemolysis, Lenalidomide supplier anemia, and sometimes bleeding. These result due to rupturing of red blood corpuscles (RBCs) leading to release of hemoglobin (Hb) into circulation; heme is produced on oxidation of Hb leading to initiation of the Fenton reaction and culminates with generation of ROS. Heme is also responsible for direct activation of TLR4, leading to autocrine secretion of ROS and TNF, and they activate the RIPK1/3-dependent necroptosis in a synergistic manner [75]. In ...

Gonadotropin-releasing hormone (GnRH) is a decapeptide hormone secreted by GnRH neurons located in the hypothalamus. It is responsible for the onset of puberty and the regulation of hormone release from the pituitary. There is a strong evidence suggesting that these GnRH neurons are intrinsically capable of generating pulsatile and episodic neurosecretion of this hormone. However, the underlying mechanism for the GnRH-pulse generator remains obscure. The discovery of GnRH receptors allowing GnRH to exert autocrine regulation on its own release, led several experimentalist in NIH to propose in 2003 a mechanism underlying this effect. We developed in 2006 a mathematical model describing the proposed mechanism, then we extended it to explain synchrony observed in GnRH neurons by incorporating the idea of a common pool of GnRH hormone. In this talk, we shall present this model and analyze several aspects of it, especially robustness. We shall show that the coupling of a heterogeneous family of GnRH ...

2390 Janus kinase 2 (JAK2) is a cytokine receptor associated tyrosine kinase. Binding of cytokines to their specific receptors leads to their dimerization and activation of associated JAKs. Activated JAKs phosphorylate specific tyrosine residues in the cytoplasmic chains of the receptor, which now act as docking sites for SH2 containing latent transcription factors known as STATs. Once bound to the receptor, STATs are activated by JAKs through phosphorylation of their tyrosine residues. Activated STATs form stable dimers and translocate to the nucleus, where they bind specific promoter sequences of their target genes involved in cell proliferation and survival, such as Bcl-xL, Bcl-2, c-myc and cyclin D1. Tumor cell lines and samples derived from hematopoetic malignancies (leukemia, lymphoma and multiple myeloma) and solid tumors (breast, head and neck, lung, prostrate and ovarian cancers) exhibit deregulated JAK-STAT signaling, which can be attributed to autocrine cytokine production or growth ...

The progression of ovarian cancer, from cell transformation through invasion of normal tissue, relies on communication between tumor cells and their adjacent stromal microenvironment. Through a natural selection process, an autocrine-paracrine communication loop establishes reciprocal reinforcement …

NovoPro offers a wide selection of tools for research on cytokines and their receptors. These include high-purity recombinant proteins, high-specific antibodies and ORF cDNA clones.. Cytokines are a large group of proteins, peptides or glycoproteins that are secreted by specific cells of immune system. Cytokines are a category of signaling molecules that mediate and regulate immunity, inflammation and hematopoiesis. Cytokines are produced throughout the body by cells of diverse embryological origin. Cytokine is a general name; other names are defined based on their presumed function, cell of secretion, or target of action. For example, cytokines made by lymphocytes can also be referred to as lymphokines, while interleukins are made by one leukocyte and act on other leukocytes. And chemokines are cytokines with chemotactic activities.. Cytokines may act on the cells that secrete them (autocrine action), on nearby cells (paracrine action), or in some instances on distant cells (endocrine ...

Autocrine hypothesis definition at Dictionary.com, a free online dictionary with pronunciation, synonyms and translation. Look it up now!

VEGF-A promoted DJM-1 cell proliferation via NRP1 in an autocrine manner. (A) A western blot shows that DJM-1 cells expressed NRP1, but not NRP2. DJM-1 cells we

Comoglio, P.M., 1988: Autocrine activation of the tyrosine kinase associated with the bombesin receptor in small cell lung carcinoma

Dictyostelium cells secrete the proteins AprA and CfaD. Cells lacking either AprA or CfaD proliferate faster than wild type, while AprA or CfaD overexpressor cells proliferate slowly, indicating that AprA and CfaD are autocrine factors that repress proliferation. CfaD interacts with AprA and requires the presence of AprA to slow proliferation. To determine if CfaD is necessary for the ability of AprA to slow proliferation, whether AprA binds to cells, and if so whether the binding requires the presence of CfaD, we examined the binding and effect on proliferation of recombinant AprA. We find that the extracellular accumulation of AprA increases with cell density and reaches a concentration of 0.3 μg/ml near a stationary cell density. When added to wild-type or aprA- cells, recombinant AprA (rAprA) significantly slows proliferation at 0.1 μg/ml and higher concentrations. From 4 to 64 μg/ml, the effect of rAprA is at a plateau, slowing but not stopping proliferation. The proliferation-inhibiting

alpha(1B)-Adrenergic receptors mediate many of the actions of the natural catecholamines, adrenaline and noradrenaline. They belong to the seven transmembrane domains G protein-coupled receptor superfamily and exert their actions mainly through activation of Gq proteins and phosphoinositide turnover/calcium signaling. Many hormones and neurotransmitters are capable of inducing alpha(1B)-adrenergic receptor phosphorylation and desensitization; among them: adrenaline and noradrenaline, phorbol esters, endothelin-I, bradykinin, lysophosphatidic acid, insulin, EGF, PDGF, IGF-I, TGF-beta, and estrogens. Key protein kinases for these effects are G protein coupled receptor kinases and protein kinase C. The lipid/protein kinase, phosphoinositide-3 kinase also appears to play a key role, acting upstream of protein kinase C. In addition to the agents employed for cells stimulation, we observed that paracrine/autocrine mediators also participate; these processes include EGF transactivation and ...

As potential autocrine or paracrine factors, extracellular nucleotides are known to be important regulators of renal ion transporters by activating cell surface receptors and intracellular signaling pathways. We investigated the influence of extracellular adenine nucleotides on Na+/H+ exchanger isoform 3 (NHE3) activity in A6-NHE3 cells. This is a polarized cell line obtained by stable transfection of A6 cells with the cDNA encoding the rat isoform of NHE3, which is expressed on the apical membrane. Basolateral addition of the P2Y(1) agonist, 2-Me-SADP, induced an inhibition of NHE3 activity, which was prevented by preincubation with selective P2Y(1) antagonists, MRS 2179 (N-6-methyl-2-deoxyadenosine-3,5-bisphosphate) and MRS 2286 (2-[2-(2-chloro-6-methylamino-purin-9-yl)-ethyl]-propane- 1,3-bisoxy(diammoniumphosphate)). NHE3 activity was also significantly inhibited by ATP and ATP-gamma-S but not by UTP. 2-Me-SADP induced a P2Y(1) antagonist-sensitive increase in both [Ca2+]i and cAMP ...

The RAF inhibitor vemurafenib (PLX4032) increases survival in patients with BRAF-mutant metastatic melanoma, but has limited efficacy in patients with colorectal cancers. Thyroid cancer cells are also comparatively refractory to RAF inhibitors. By contrast to melanomas, inhibition of MAPK signaling by vemurafenib is transient in thyroid and colorectal cancer cells. The rebound in ERK in thyroid cells is accompanied by increased HER3 signaling caused by induction of HER3 transcription through decreased promoter occupancy by the transcriptional repressors CtBP1 and 2, and by autocrine secretion of neuregulin-1. The HER kinase inhibitor lapatinib prevents MAPK rebound and sensitizes BRAF-mutant thyroid cancer cells to RAF or MEK inhibitors. This provides a rationale for combining ERK pathway antagonists with inhibitors of feedback-reactivated HER signaling in this disease. The determinants of primary resistance to MAPK inhibitors vary between cancer types, due to preferential upregulation of ...

Eosinophils are major effector cells in type 2 inflammatory responses and become activated in response to IL-4 and IL-33, yet the molecular mechanism remains unclear. We examined the direct effect of these cytokines on eosinophils and demonstrated that murine eosinophils respond to IL-4 and IL-33 by phosphorylation of STAT-6 and NFkB, respectively. RNA sequencing analysis of murine eosinophils indicated that IL-33 regulates 519 genes, whereas IL-4 regulates only 28 genes, including 19 IL-33-regulated genes. Interestingly, IL-33 induced eosinophil activation via two distinct mechanisms, IL-4 independent and IL-4 secretion/auto-stimulation dependent. Anti-IL-4 or anti-IL-4Ra antibody-treated eosinophils, as well as Il4- or Stat6-deficient eosinophils, had attenuated protein secretion of a subset of IL-33-induced genes, including Retnla and Ccl17. However, the induction of most IL-33-regulated transcripts (e.g. Il6 and Il13) was IL-4 independent and blocked by NFkB inhibition. Indeed, IL-33 induced the

Th17 cells are critically involved in autoimmune disease induction and severity. Recently, we showed that Th17 cells from patients with rheumatoid arthritis (RA) directly induced a proinflammatory loop upon interaction with RA synovial fibroblasts (RASF), including increased autocrine IL-17A production. To unravel the mechanism driving this IL-17A production, we obtained primary CD4+CD45RO+CCR6+ (Th17) cells and CD4+CD45RO+CCR6− (CCR6−) T cells from RA patients or healthy individuals and cocultured these with RASF. IL-1β, IL-6, IL-23p19, and cyclooxygenase (COX)-2 expression and PGE2 production in Th17-RASF cultures were higher than in CCR6− T cell-RASF cultures. Cytokine neutralization showed that IL-1β and IL-6, but not IL-23, contributed to autocrine IL-17A induction. Importantly, treatment with celecoxib, a COX-2 inhibitor, resulted in significantly lower PGE2 and IL-17A, but not IFN-γ, production. Combined celecoxib and TNF-α blockade more effectively suppressed the ...

Epigenetics is the study of cellular information other than the DNA sequence itself, which is heritable in cell progeny and involves modification of DNA or its associated proteins. Epigenetic changes include DNA methylation, a covalent modification of cytosine, and post-translational modifications of histone tails, such as acetylation, methylation, and phosphorylation (1). Epigenetic alterations have been increasingly recognized as an important mechanism in tumorigenesis since their discovery in human tumors in 1983 (2, 3). Genomic imprinting is an epigenetic modification of a specific parental chromosome in the gamete or zygote, leading to parental origin-specific differential expression of the two alleles of a gene in somatic cells of the offspring (3).. The insulin-like growth factor-II gene (IGF2), an imprinted gene with parental allele expressed and maternal allele silenced, is an important autocrine growth factor in tumors due to its mitogenic and antiapoptotic functions mediated by the ...

Epithelial cells are unable to grow or survive when they lose contact with appropriate ECM proteins. However, transformation by the Ras oncoprotein bypasses the need for signals from adhesion receptors and protects them from undergoing apoptosis. Ras‐dependent survival in other systems is known to have two effectors, PI 3‐K and Raf, the latter of which functions by activating the ERK (a MAPK) pathway. To address the contribution of ERK, J. Downward (London, UK) used an inducible active form of Raf to monitor early changes in gene transcription that impart protection from detachment‐induced apoptosis. Among the genes that are strongly up‐regulated by activated Raf are the autocrine factors HB‐EGF, amphiregulin and TGFα. All of these are members of the epithelial growth factor (EGF) family, indicating that protection by Raf is dependent on the function of an autocrine loop involving transcriptional induction of cell survival EGF‐like factors. Interestingly, Raf‐dependent survival is ...

In light of the poor control of malignant mesothelioma by approved cytotoxic chemotherapeutic regimens, RTKs have been actively explored in MPM as alternative therapeutic targets (15, 19, 42, 43). Although EGFR, VEGFRs, MET, and PDGFRs have been a focus in these studies, our findings support the novel role of FGFR1 as a growth driver in a subset of MPM cell lines and suggest that FGFR-active TKIs may serve as therapeutics in this cancer. RNAi-mediated silencing of FGFR1 inhibited clonogenic growth of two FGFR1-expressing MPM cell lines, H226 and MSTO211H (Fig. 4), and the TKI, ponatinib, selectively inhibited growth of MPM cell lines expressing FGFR1 (Fig. 2). We previously demonstrated with RNAi-mediated silencing the requirement of FGF2 for H226 cell growth (35), and we validate this finding by showing sensitivity of FGFR1-dependent mesothelioma cell lines to the ligand trap, FP-1039. Combined, the data support the activity of an FGF-FGFR1 autocrine pathway in a subset of mesothelioma cell ...

Platelet-derived growth factor (PDGF), a potent mitogen for mesenchymal cells, elicits its effects by binding to cell surface tyrosine kinase receptors, denoted α- and β-receptors. This thesis describes the mechanism of interaction between stimulated PDGF receptors and various intracellular molecules.. PDGF-B is homologous to the transforming protein v-sis encoded by the simian sarcoma virus (SSV). Transformation of cells by the v-sis oncogene occurs through an autocrine mechanism, whereby the v-Sis protein produced by a cell activates the cells own PDGF receptors. We investigated the subcellular location of the autocrine signal and found that in c-Sis/B-chain transformed cells, autophosphorylated intracellular receptors initiated activation of phosphatidylinositol 3 kinase, and tyrosine phosphorylation of phospholipase C-γ (PLC-γ) and Ras GTPase-activating protein (RasGAP). These signals were, however, not sufficient for transformation of the cells.Receptor-association with Grb2 and SHP-2, ...

TY - JOUR. T1 - Autocrine effect of Zn2+ on the glucose-stimulated insulin secretion. AU - Slepchenko, Kira G.. AU - Daniels, Nigel A.. AU - Aili, Guo. AU - Li, Yang V.. PY - 2015/9/25. Y1 - 2015/9/25. N2 - It is well known that zinc (Zn2+) is required for the process of insulin biosynthesis and the maturation of insulin secretory granules in pancreatic beta (β)-cells, and that changes in Zn2+ levels in the pancreas have been found to be associated with diabetes. Glucose-stimulation causes a rapid co-secretion of Zn2+ and insulin with similar kinetics. However, we do not know whether Zn2+ regulates insulin availability and secretion. Here we investigated the effect of Zn2+ on glucose-stimulated insulin secretion (GSIS) in isolated mouse pancreatic islets. Whereas Zn2+ alone (control) had no effect on the basal secretion of insulin, it significantly inhibited GSIS. The application of CaEDTA, by removing the secreted Zn2+ from the extracellular milieu of the islets, resulted in significantly ...

The present study examined the EP subtypes involved. In primary cultures of rat IMCD cells, EP4 antagonism with structurally distinct EP4 antagonists completely abolished Ang II-induced PRR expression, and EP4 agonism alone elevated the expression. In Sprague-Dawley rats, EP4 antagonism effectively suppressed the increases in renal medullary PRR expression, renal medullary and urinary renin levels, as well as blood pressure in response to Ang II infusion. Interestingly, in vitro data also suggested involvement of the EP1 but not the EP3 subtype in Ang II-induced PRR expression.. PGE2 is a major prostanoid produced in the kidney, particularly in the CD. As an autocrine/paracrine factor, PGE2exerts a diverse range of action at the site of its production, affecting renal medullary blood flow and tubular sodium and water transport, as well as cell survival.26,27 The biological action of PGE2 is mediated by 4 distinct EP4 receptors (EP1-4). We for the first time demonstrated a dominant role of the ...

Cytokines are small, secreted, glycoproteins that specifically affect the interactions and communications between cells. Cytokines are produced transiently and locally, acting in a paracrine or autocrine manner, and they are extremely potent, ligating high affinity cell surface receptors to elicit changes in gene expression and protein synthesis in the responding cell. Cytokines produced during the differentiation of T follicular helper (Tfh) cells and B cells within the germinal center (GC) niche play an important role in ensuring that the humoral immune response is robust, whilst retaining flexibility, during the generation of affinity matured antibodies. Cytokines produced by B cells, antigen presenting cells and stromal cells are important for the differentiation of Tfh cells and Tfh cell produced cytokines act both in an autocrine fashion to firm Tfh cell differentiation and in a paracrine fashion to support the differentiation of memory B cells and plasma cells. In this review, we discuss the role

The transforming growth factor α (TGFα) epidermal growth factor receptor (EGFR) autocrine pathway plays a key role in the development and progression of human epithelial cancers (1). Overexpression of TGFα and/or EGFR has been detected in the majority of human carcinomas, has been associated with resistance to cytotoxic drugs and to hormone therapy, and is generally an indicator of poor prognosis (1). For these reasons, the blockade of the EGFR-driven autocrine pathway has been proposed as a target for anticancer therapy (2). Several pharmacologic approaches have been developed for blocking EGFR. The two most successful approaches for the treatment of cancer patients have been thus far the anti-EGFR-blocking monoclonal antibodies (MAb), such as Cetuximab, and the selective EGFR small molecule tyrosine kinase inhibitors (TKI), such as Gefitinib and Erlotinib (3-5).. Tumor angiogenesis is the process leading to the formation of blood vessels within a tumor and plays a key role in cancer cell ...

IFN-γ is a well-characterized macrophage differentiation signal. Macrophages pretreated with IFN-γ achieve a higher level of activation, e.g., IFN-γ-primed macrophages become more sensitive to other stimuli, such as bacterial products and cytokines, as evidenced by the synergistic induction of many inflammatory gene products, e.g., iNOS (12)(35)(36) and IL-12 p40 (13)(37)(42)(43). In this paper, we show that activation with IFN-γ, as well as its priming effect, can be extended to Cox-2, another gene with a central role in inflammatory responses. Although IFN-γ regulation of Cox-2 has been described previously (26)(44)(45), little is known of the molecular mechanisms that underlie activation of this gene by IFN-γ. For example, in bronchial epithelial cells (44) and in normal human epidermal keratinocytes (26), Cox-2 induction is controlled through autocrine loops via the epidermal growth factor receptor and its ligands, such as TGF-α, resulting in a delayed activation. However, in ...

BMP4 regulates development of many smooth muscle targets by promoting differentiation, organization, and maturation of smooth muscle cells. Typically, BMP4 from adjacent epithelium, endothelium, or fibroblasts acts in a paracrine manner to regulate smooth muscle development (Frank et al., 2005; Cai, 2009; Wang et al., 2009; Tasian et al., 2010). Our findings show that, in the adult, vaginal smooth muscle cells themselves synthesize BMP4, raising the possibility that BMP4 may also act in an autocrine manner. Indeed, a recent report suggests that BMP4 exerts autocrine effects by promoting C2C12 cell myotube formation (Umemoto et al., 2011). Hence, BMP4 may regulate smooth muscle integrity and function beyond the developmental period.. Smooth muscle cells are generally well innervated and, accordingly, secrete proteins that potentially influence axon growth and integrity. These include neurotrophins, extracellular matrix components, growth factors, and cytokines (Weintraub et al., 1996; Knox et ...

JAK/STAT3 is one of the major signaling pathways that is aberrantly activated in ovarian cancer and associated with tumor progression and poor prognosis in patients with ovarian cancer. In this study, we evaluated the therapeutic potential of targeting JAK/STAT3 signaling in ovarian cancer using a peritoneal dissemination mouse model. We developed this mouse model by injecting a metastatic human ovarian cancer cell line, SKOV3-M-Luc, into the peritoneal cavity of immunodeficient mice. This model displayed a phenotype similar to late-stage ovarian cancer, including extensive peritoneal metastasis and ascites production. The constitutive activation of STAT3 in human ovarian cancer cells appeared to be mediated by an autocrine cytokine loop involving the IL6 family of cytokines and JAK1 kinase. shRNA-mediated knockdown of JAK1 or STAT3 in ovarian cancer cells led to reduced tumor growth, decreased peritoneal dissemination, and diminished ascites production, suggesting a critical role of STAT3 in ...

Cytokines Cytokines are a group of regulatory proteins critically involved in many physiological processes such as immune recognition, cell differentiation and cell proliferation. They have been identified in many vertebrate species and are produced by a variety of different cell types. Cytokines are usually produced transiently and locally, acting in a paracrine or autocrine manner. They interact with high affinity cell surface receptors specific for each cytokine or cytokine group and are active at very low concentrations mostly in the picogram range.

Cytokines Cytokines are a group of regulatory proteins critically involved in many physiological processes such as immune recognition, cell differentiation and cell proliferation. They have been identified in many vertebrate species and are produced by a variety of different cell types. Cytokines are usually produced transiently and locally, acting in a paracrine or autocrine manner. They interact with high affinity cell surface receptors specific for each cytokine or cytokine group and are active at very low concentrations mostly in the picogram range.

If these conditions are met, the CD4+ T cell will release IFN-γ to stimulate the APC to efficiently kill its pathogen. The CD4+ T cell will also release IL-2 to (1) cause activation and proliferation of CD8+ cytotoxic T cells to kill virally infected host cells, and (2) cause CD4+ T cell proliferation and differentiation in an autocrine manner. ...