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At least 415 records · Page 23Linked to original sources
PubMed2006

The antiapoptotic effect of IL-6 autocrine loop in a cellular model of advanced prostate cancer is mediated by Mcl-1.

Levels of the proinflammatory cytokine interleukin-6 (IL-6) are increased in therapy-resistant prostate cancer. IL-6 has been considered a positive growth factor in late-stage prostate cancer cells and a potential target for therapeutic interference. Effects of inhibition of IL-6 on cell survival were studied in LNCaP-IL6+ cells, a model system for advanced prostate cancer, which produce IL-6. We show that the autocrine IL-6 loop is responsible for resistance to apoptosis and increased cellular levels of myeloid cell leukemia-1 (Mcl-1) protein, an antiapoptotic member of the Bcl-2 family. Treatment of cells with a chimeric anti-IL-6 antibody (CNTO 328) led to the induction of apoptosis and downregulation of Mcl-1 protein levels. Specific knockdown of Mcl-1 gene expression by small interfering RNA also yielded an increase in apoptosis of LNCaP-IL-6+ cells. Vice versa, inactivation of IL-6 autocrine loop had no influence on apoptosis levels in the absence of Mcl-1, thus suggesting this molecule as a mediator of the survival action of IL-6. Mcl-1 protein regulation by the endogenous cytokine directly involved the extracellular signal-regulated kinase 1/2 mitogen-activated protein kinase pathway. Our data support the concept of anti-IL-6 targeted therapy in therapy-resistant prostate cancer.

Antibodies, Monoclonal↗
PubMed2006

Rho/ROCK-dependent pseudopodial protrusion and cellular blebbing are regulated by p38 MAPK in tumour cells exhibiting autocrine c-Met activation.

BACKGROUND INFORMATION: The c-Met-dependent, beta-actin-rich, blebbed pseudopodia of MSV-MDCK-INV (invasive Moloney-sarcoma-virus-transformed Madin-Darby canine kidney) cells are induced by Rho/ROCK (Rho kinase) activation, and are morphologically distinct from flat extended lamellipodia. RESULTS: Microtubules were shown to extend to these actin-rich pseudopodial domains, and microtubule depolymerization by nocodazole treatment resulted in progressive cellular blebbing, initiating in the pseudopodial domains and resulting in transient cellular rounding and blebbing after 30 min. The blebbing response was dependent on autocrine HGF (hepatocyte growth factor) activation of c-Met and prevented by inhibition of RhoA, ROCK and p38 MAPK (p38 mitogen-activated protein kinase), but not ERK (extracellular-signal-regulated kinase) or PI3K (phosphoinositide 3-kinase). Phospho-p38 MAPK was present in pseudopodia, localizing activation of this signalling pathway to this protrusive membrane structure. In serum-starved cells, LPA (lysophosphatidic acid) activation of RhoA induced p38 MAPK-dependent pseudopodial protrusions, and inhibition of p38 MAPK prevented pseudopodial protrusion and displacement of MSV-MDCK-INV cells. MSV-MDCK-INV cells exhibited intermittent blebbing and rounding, which may represent an integral part of their motile behaviour. CONCLUSIONS: The localized activation of an autocrine HGF/c-Met loop regulates Rho/ROCK activation of p38 MAPK signalling to stimulate both membrane blebbing and pseudopod formation.

Animals↗
PubMed2001

Interleukin-13 and interleukin-13 receptor in Hodgkin's disease: possible autocrine mechanism and involvement in fibrosis.

AIMS: Hodgkin's disease (HD) is characterized by the presence of Hodgkin and Reed-Sternberg (H-RS) cells against a hyperplastic background of reactive cells such as lymphocytes, histiocytes, plasma cells, eosinophils, neutrophils, and stromal cells. There is ample evidence to suggest that proliferation and survival of HD-derived cells is due to cytokine signalling. Recently, high expression of interleukin (IL)-13 was described in HD-derived cell lines. Here we investigated the possible involvement of IL-13 in the pathophysiology, especially autocrine pathways of H-RS cells. METHODS AND RESULTS: The expression of IL-13 and IL-13 receptor (IL-13R) was determined by immunostaining and reverse transcriptase-polymerase chain reaction in 39 cases of HD, including 17 cases with nodular sclerosis (NS) type, 19 cases with mixed cellularity (MC), and three cases with lymphocyte predominance (LP) type. Expression of IL-13 was confined to H-RS cells and a few lymphocytes. IL-13R was expressed in H-RS cells, lymphocytes, histiocytes, fibroblasts, and endothelial cells. H-RS cells of MC and NS types frequently expressed both IL-13 and IL-13R. However, the number of IL-13-positive H-RS cells was statistically higher in NS-type than in MC-type, but the number of IL-13R was similar. IL-13R-positive fibroblasts were frequently encountered in NS-type. H-RS cells of LP type rarely expressed IL-13. CONCLUSIONS: Our results suggest that IL-13 might be involved in autocrine pathways of H-RS cells and fibrosis at least in NS-type. Our results also indicated that in addition to the morphological and phenotypic differences, the neoplastic cells of LP type might be functionally different from H-RS cells of MC- and NS-types.

Adolescent↗
PubMed2001

Sites of epidermal growth factor synthesis and action in the pituitary: paracrine and autocrine interactions.

1. Epidermal growth factor (EGF) is produced by growth hormone (GH) cells and gonadotropes in normal pituitary cell populations. The studies were initiated to determine whether EGF is a paracrine or autocrine regulator of gonadotrope function. 2. The first group of studies tested for the presence of EGF receptors in gonadotropes from cycling female rats by immunolabelling. Expression varied with the stage of the cycle. At the highest point (metoestrus), only a few EGF target cells are gonadotropes, identified by their content of luteinizing hormone (LH)-beta mRNA. Expression by gonadotropes then increased to reach a peak of 50% of cells during pro-oestrus. 3. Studies investigating the regulation of expression of EGF receptor (R) showed that all culture conditions (in media with or without serum) and EGF itself both stimulated expression of the receptor by gonadotropes in populations from oestrus or metoestrus rats. Gonadotropin-releasing hormone (GnRH) also stimulated EGFR expression in follicle-stimulating hormone (FSH) gonadotropes from oestrus animals. Additional tests of expression of immediate early genes (c-fos) showed that, after 15 min, EGF stimulated expression in cells with FSH antigens. 4. Epidermal growth factor also stimulated gonadotrope proliferation, as detected by the MTT cell growth/cell death assays and bromodeoxyuridine uptake by gonadotropes during the S phase (DNA synthesis) of the cell cycle. 5. Epidermal growth factor and GnRH both stimulated a significant increase in the percentage of mitotic gonadotropes. Epidermal growth factor may be an autocrine or a paracrine growth factor to maintain and develop the gonadotrope population and EGF may also be involved in early differentiation events that prepare cells to support the LH surge.

Animals↗
PubMed1999

Changes in muscle mass and phenotype and the expression of autocrine and systemic growth factors by muscle in response to stretch and overload.

The study of the underlying mechanisms by which cells respond to mechanical stimuli, i.e. the link between the mechanical stimulus and gene expression, represents a new and important area in the morphological sciences. Several cell types ('mechanocytes'), e.g. osteoblasts and fibroblasts as well as smooth, cardiac and skeletal muscle cells are activated by mechanical strain and there is now mounting evidence that this involves the cytoskeleton. Muscle offers one of the best opportunities for studying this type of mechanotransduction as the mechanical activity generated by and imposed upon muscle tissue can be accurately controlled and measured in both in vitro and in vivo systems. Muscle is highly responsive to changes in functional demands. Overload leads to hypertrophy, whilst decreased load force generation and immobilisation with the muscle in the shortened position leads to atrophy. For instance it has been shown that stretch is an important mechanical signal for the production of more actin and myosin filaments and the addition of new sarcomeres in series and in parallel. This is preceded by upregulation of transcription of the appropriate genes some of which such as the myosin isoforms markedly change the muscle phenotype. Indeed, the switch in the expression induced by mechanical activity of myosin heavy chain genes which encode different molecular motors is a means via which the tissue adapts to a given type of physical activity. As far as increase in mass is concerned, our group have cloned the cDNA of a splice variant of IGF-1 that is produced by active muscle that appears to be the factor that controls local tissue repair, maintenance and remodelling. From its sequence it can be seen that it is derived from the IGF-1 gene by alternative splicing but it has different exons to the liver isoforms. It has a 52 base insert in the E domain which alters the reading frame of the 3' end. Therefore, this splice variant of IGF-1 is likely to bind to a different binding protein which exists in the interstitial tissue spaces of muscle, neuronal tissue and bone. This would be expected to localise its action as it would be unstable in the unbound form which is important as its production would not disturb the glucose homeostasis unduly. This new growth factor has been called mechano growth factor (MGF) to distinguish it from the liver IGFs which have a systemic mode of action. Although the liver is usually thought of as the source of circulating IGF-1, it has recently been shown that during exercise skeletal muscle not only produces much of the circulating IGF-1 but active musculature also utilises most of the IGF-I produced. We have cloned both an autocrine and endocrine IGF-1, both of which are upregulated in cardiac as well as skeletal muscle when subjected to overload. It has been shown that, in contrast to normal muscle, MGF is not detectable in dystrophic mdx muscles even when subjected to stretch and stretch combined with electrical stimulation. This is true for muscular dystrophies that are due to the lack of dystrophin (X-linked) and due to a laminin deficiency (autosomal), thus indicating that the dystrophin cytoskeletal complex may be involved in the mechanotransduction mechanism. When this complex is defective the necessary systemic as well as autocrine IGF-1 growth factors required for local repair are not produced and the ensuing cell death results in progressive loss of muscle mass. The discovery of the locally produced IGF-1 appears to provide the link between the mechanical stimulus and the activation of gene expression.

Adaptation, Physiological↗
PubMed2001

An autocrine loop mediates expression of vascular endothelial growth factor in human dermal microvascular endothelial cells.

The expression of vascular endothelial growth factor mRNA and protein is regulated by a number of agents including growth factors, cytokines, and phorbol esters. Here we report that vascular endothelial growth factor is able to increase its own level in cultured human dermal microvascular endothelial cells. Accumulation of vascular endothelial growth factor mRNA and polypeptide can be detected as early as 4 h after addition of vascular endothelial growth factor to the cell culture medium. The autocrine action of vascular endothelial growth factor appears to be mediated by the KDR receptor. The increase of its own message by vascular endothelial growth factor is blocked by the transcription inhibitor actinomycin D. Transient transfection experiments performed with human dermal microvascular endothelial cells and using a 3.2 kb human vascular endothelial growth factor promoter fragment showed that vascular endothelial growth factor auto-induction can be mimicked at the promoter level. This indicates that the observed vascular endothelial growth factor mRNA increase after vascular endothelial growth factor treatment is occurring at the level of transcription. Furthermore, vascular endothelial growth factor auto-induction is inhibited by PD 098059, showing that phosphorylation events, catalyzed by mitogen activated protein kinases, are a prerequisite for the vascular endothelial growth factor effect. Examination of extracellular signal-regulated kinase and c-Jun N-terminal protein kinase catalytic activities showed that both enzymes have to be activated to mediate the vascular endothelial growth factor signal. Our data demonstrate for the first time the existence of an autocrine loop for vascular endothelial growth factor in endothelial cells. Most probably this represents an amplification mechanism for the action of vascular endothelial growth factor in the microvascularization process.

Autocrine Communication↗
PubMed2001

Autocrine motility factor enhances hepatoma cell invasion across the basement membrane through activation of beta1 integrins.

Autocrine motility factor/phosphohexose isomerase (AMF/PHI) is a cytokine that is linked to tumor invasion and metastasis. In hepatocellular carcinoma (HCC) tissues, hepatoma cells produce AMF/PHI and its receptor, Mr 78,000 glycoprotein (gp78), is strongly detected in hepatoma cells invading into the stroma and tumor thrombi in the portal vein. Here, we investigated the mechanism of hepatoma cell invasion through Matrigel induced by AMF/PHI using 3 hepatoma cell lines. Production of AMF/PHI, phosphorylation of MEK1/2, and Rho activity were investigated by immunoblotting. Expression of AMF/PHI and gp78 was observed by confocal fluorescence microscopy. The influence of AMF/PHI on activated integrin beta1 subunit expression was evaluated by flow cytometry. Changes in invasion, adhesion, and motility induced by AMF/PHI were evaluated using chemoinvasion, adhesion, and phagokinetic track motility assays. The effect of AMF/PHI on matrix metalloproteinase (MMP) secretion was evaluated by gelatin zymography. Hepatoma cells produced AMF/PHI and expressed gp78. Although AMF/PHI was ubiquitously detected, gp78 was strongly expressed in migrating cells. AMF/PHI induced up-regulation of activated integrin beta1 subunit expression. AMF/PHI stimulated hepatoma cell invasion through Matrigel, and stimulated the adhesion, motility, and MMP-2 secretion of hepatoma cells. The latter effects were suppressed by the function-blocking antibody for integrin beta1 subunit. AMF/PHI also enhanced Rho activity and the phosphorylation of MEK1 and MEK 2. Our results indicate that AMF/PHI enhances hepatoma cell invasion through Matrigel in an autocrine manner by stimulating the adhesion, motility, and MMP-2 secretion of these cells through activation of beta1 integrins.

Basement Membrane↗
PubMed2002

Adrenocortical peptides: autocrine or paracrine regulators for the steroid hormone secretion or the cell proliferation?

There is accumulating evidence that indicates the production and secretion of some peptides by adrenal cortex and adrenocortical tumors. These peptides include adrenomedullin, proadrenomedullin N-terminal 20 peptide (PAMP), endothelin-1, cerebellin, urotensin-II etc., and appear to be involved in the regulation of steroid hormone secretion and the proliferation of adrenocortical cells as autocrine and/or paracrine factors. It is noteworthy that expression of adrenomedullin is induced by hypoxia and inflammatory cytokines in various cells, raising the possibility that the adrenocortical production of adrenomedullin (and probably PAMP) may be increased in some inflammatory and/or ischemic conditions, and these two peptides may modulate the states of inflammatory and/or ischemic disorders. In addition to adrenomedullin and PAMP, adrenal cortex and/or some adrenocortical tumors express endothelin-1, cerebellin, urotensin-II, etc. The adrenocortical peptides may form a novel autocrine or paracrine regulatory system for the steroid hormone secretion and the cell proliferation in the adrenal cortex, and involve in the pathophysiology of inflammatory, ischemic or neoplastic diseases of the adrenal cortex

Adrenal Cortex↗
PubMed2006

Angiopoietin-2 functions as an autocrine protective factor in stressed endothelial cells.

Angiopoietin (Ang)-2, a context-dependent agonist/antagonist for the vascular-specific Tie2 receptor, is highly expressed by endothelial cells at sites of normal and pathologic angiogenesis. One prevailing model suggests that in these settings, Ang-2 acts as an autocrine Tie2 blocker, inhibiting the stabilizing influence of the Tie2 activator Ang-1, thereby promoting vascular remodeling. However, the effects of endogenous Ang-2 on cells that are actively producing it have not been studied in detail. Here, we demonstrate that Ang-2 expression is rapidly induced in endothelial cells by the transcription factor FOXO1 after inhibition of the phosphatidylinositol 3-kinase/Akt pathway. We employ RNAi and blocking antibodies to show that in this setting, Ang-2 unexpectedly functions as a Tie2 agonist, bolstering Akt activity so as to provide negative feedback on FOXO1-regulated transcription and apoptosis. In addition, we show that Ang-2, like Ang-1, activates Tie2/Akt signaling in vivo, thereby inhibiting the expression of FOXO1 target genes. Consistent with a role for Ang-2 as a Tie2 activator, we demonstrate that Ang-2 inhibits vascular leak. Our data suggests a model in which Ang-2 expression is induced in stressed endothelial cells, where it acts as an autocrine Tie2 agonist and protective factor.

Androstadienes↗
PubMed1998

Stretch activates Jun N-terminal kinase/stress-activated protein kinase in vascular smooth muscle cells through mechanisms involving autocrine ATP stimulation of purinoceptors.

Mechanical strain has been implicated in phenotypic changes, including alteration of gene expression in vascular smooth muscle cells; however, the molecular basis for mechanotransduction leading to nuclear gene expression is largely unknown. We demonstrate in the present study that cyclic stretching of vascular smooth muscle cells dramatically activates Jun N-terminal kinase (JNK)/stress-activated protein kinase (SAPK) through an autocrine mechanism. Stretch causes time- and strength-dependent rise of the ATP concentration in media. The stretch-induced activation JNK/SAPK is attenuated by the addition of hexokinase or apyrase that scavenge ATP in media. Both the P2 receptor antagonist and the A1 subtype-selective P1 receptor antagonist partially inhibit stretch-induced activation of JNK/SAPK. The conditioned medium from stretched cells contains an activity to stimulate JNK/SAPK. The JNK-stimulating activity in the conditioned medium from stretched cells is attenuated by the addition of apyrase or P1 and P2 receptor antagonists. The addition of exogenous ATP or adenosine induces dose-dependent activation of JNK/SAPK. These results indicate that stretch activates JNK/SAPK in vascular smooth muscle cells through mechanisms involving autocrine stimulation of purinoceptors by ATP and its hydrolyzed product adenosine.

Adenosine Triphosphate↗
PubMed1998

Autocrine regulation of macrophage differentiation and 92-kDa gelatinase production by tumor necrosis factor-alpha via alpha5 beta1 integrin in HL-60 cells.

Tumor necrosis factor-alpha (TNF-alpha) gene is one of the early response genes induced by phorbol 12-myristate 13-acetate (PMA) in human HL-60 myeloid leukemia cells. In the present study, we examined the role of the TNF-alpha autocrine loop in PMA-induced macrophage differentiation and gene expression of 92- and 72-kDa gelatinases (MMP-9 and MMP-2). In HL-60 cells, PMA inhibited cell proliferation and induced cell adhesion and spreading, expression of surface maturation marker OKM1 and phagocytic activity, as well as the expression of both gelatinases, which all characterize the macrophage phenotype. In contrast, TNF-alpha alone was only effective in inhibiting cell proliferation. Blocking the endogenous TNF-alpha activity with neutralizing anti-TNF-alpha antibodies abolished all these PMA-induced events with the exception of MMP-2 gene expression. Since fibronectin (FN)-mediated cell adhesion and spreading are prerequisite for both macrophage differentiation and MMP-9 gene expression in HL-60 cells, we hypothesized that TNF-alpha might be involved in modulating the expression of either the FN or its integrin receptor genes. Whereas PMA substantially enhanced the steady state mRNA and protein levels of both FN and alpha5 beta1 integrins, TNF-alpha alone had little effect on the expression of these genes. However, anti-TNF-alpha antibodies blocked PMA-induced augmentation of both alpha5 and beta1 integrin gene expression without affecting the expression of the FN gene. Our results suggest that TNF-alpha may regulate macrophage differentiation and critical matrix-degrading activities of myeloid progenitor cells in an autocrine manner by augmenting surface levels of the alpha5 beta1 integrin, thus promoting interactions with the extracellular matrix, a key event for maturation and migration of these cells during inflammation.

Autocrine Communication↗
PubMed2004

Autocrine transforming growth factor alpha regulates cell adhesion by multiple signaling via specific phosphorylation sites of p70S6 kinase in colon cancer cells.

Recently, we showed that autocrine transforming growth factor alpha (TGFalpha) controls the epidermal growth factor receptor (EGFR)-mediated basal expression of integrin alpha2, cell adhesion and motility in highly progressed HCT116 colon cancer cells. We also reported that the expression of basal integrin alpha2 and its biological effects are critically controlled by the constitutive activation of the ERK/MAPK pathway (Sawhney, R. S., Sharma, B., Humphrey, L. E., and Brattain, M. G. (2003) J. Biol. Chem. 278, 19861-19869). In the present report, we further examine the downstream signaling mechanisms underlying EGFR/ERK signaling and integrin alpha2 function in HCT116 cells. Selective MEK inhibitors attenuated TGFalpha-mediated basal activation of p70S6K (S6K) specifically at Thr-389, indicating that this S6K site is downstream of ERK/MAPK signaling. Cells were treated with the selective protein kinase C (PKC) inhibitor bisindolylmaleimide to determine the role of PKC in S6K activation. The Thr-421 and Ser-424 phosphorylation sites of S6K were specifically inhibited by bisindolylmaleimide, which also blocked integrin alpha2 expression, cell adhesion, and motility. These data establish a novel cell motility function of S6K via PKC activation in a cancer cell. In addition, we examined whether mammalian target of rapamycin signaling controls S6K activation. Rapamycin inhibited constitutive S6K phosphorylation specifically at Thr-389, Thr-421, and Ser-424 sites. The assignment of these phosphorylation sites on S6K to biological functions was unequivocally confirmed by transfection of cells with specific single phosphorylation site dominant negative mutants. These experiments show for the first time that autocrine TGFalpha regulates cell adhesion function by multiple signaling pathways via specific phosphorylation sites of S6K in cancer cells.

Autocrine Communication↗
PubMed2004

Coexpression of CD40 and CD40L on B lymphoma and carcinoma cells: an autocrine anti-apoptotic role.

To evaluate a possible autocrine role of CD40L, the expression and functional activity of CD40L on NHL and breast carcinoma cell lines were investigated. Using flow cytometry, CD40 was consistently detectable at the surface of all 5 NHL cell lines tested. CD40L expression was detectable at the surface of DAUDI (54%, MFI 47) and BJAB (12%, MFI 32) cell lines, and marginally on the RAJI cell line (7%, MFI 30), while 4 of 5 NHL cell lines (DAUDI, RAJI, BJAB, BL70) had detectable CD40L mRNA. CD40 was expressed on T47D and BT20 breast carcinoma cell lines while CD40L was detectable on T47D (93%, MFI 137) only. Both BT20 and T47D had detectable CD40 mRNA, while CD40L mRNA was detectable only in the T47D cell line. CD40, but not CD40L, was detectable on 6 renal, 1 prostatic and 1 colon carcinoma cell lines. CD40L expressed on tumor cells was functional, as shown by its capacity to decrease drug-induced apoptosis on CD40 expressing NHL and breast carcinoma cell lines, while irradiated CD40L negative cell line (BT20) had no effect. Blocking CD40L antibody abrogated the protective effect of irradiated CD40L positive T47D cell line against drug-induced apoptosis on BL70 cell line, confirming that CD40L is functional in the DAUDI and T47D cell lines. Importantly, blocking CD40L antibody increased drug-induced apoptosis in CD40L positive cell lines but had no effect on the CD40L negative cell lines. CD40L is expressed on CD40 positive B NHL and breast carcinoma cell lines and induces an autocrine antiapoptotic signal when cells are exposed to cytotoxic agents.

Antibodies, Blocking↗
PubMed2006

Disease-specific expression of VEGF and its receptors in AML cells: possible autocrine pathway of VEGF/type1 receptor of VEGF in t(15;17) AML and VEGF/type2 receptor of VEGF in t(8;21) AML.

Various angiogenic factors, such as vascular endothelial growth factor (VEGF) and an associated molecule, placenta growth factor (PlGF), are thought to be important for normal and malignant hematopoiesis. This study examined mRNA expression of VEGF, PlGF and receptors for these molecules in AML cells and identified the disease-specific patterns of expression. AML M3 having t(15;17) abnormality showed highest expression of VEGF and VEGF receptor type 1 (VEGFR1), suggesting the autocrine pathway of VEGF-VEGFR1. Then, t(8;21) AML demonstrated augmented expression of VEGF and VEGF receptor type 2 (VEGFR2), suggesting VEGF-VEGFR2 autocrine pathway. Then, addition of VEGFR2 kinase inhibitor in Kasumi-1, a t(8;21) AML cell line, resulted in marked inhibition of cell growth, although growth inhibitory effect of R2 kinase inhibitor to HL-60 was marginal. In addition, cell cycle analysis study showed S-phase cell population reduction by R2 kinase inhibitor in Kasumi-1, but not in HL-60. This observation is thought to be the rationale for novel molecular target therapy directed to angiogenic molecules.

Adult↗
PubMed2005

Eosinophils from asthmatics release IL-5 in an autocrine fashion to prevent apoptosis through upregulation of Bcl-2 expression.

Interleukin (IL)-5 plays an important role in maintaining the survival of eosinophils via the specific alpha-subunit of its receptor. Apoptosis, a form of programmed cell death, is thought to represent a mechanism that promotes the resolution of eosinophilic inflammation in asthma. The aim of our present study is to investigate whether IL-5 acts in an autocrine fashion on eosinophil apoptosis in asthmatics. Immunoreactivities of intracellular IL-5 and IL-5 receptor alpha-subunit (Ralpha) were detected uniquely on the eosinophils. The magnitude of IL-5 and IL-5 Ralpha expression on eosinophils was significantly higher in asthmatics than that of normal subjects (p<0.05) determined by flow cytometry. Apoptosis of eosinophils was measured by the propidium iodide staining method and DNA ladder. The percent of apoptotic eosinophils from asthmatics was significantly increased by coincubation with anti-hIL-5 Ralpha Ab (0.1, 0.5, and 2.5 microg/mL) for 1, 2, or 16 hours than was those of corresponding controls (p<0.05, n=8). However, there was no significant effect of anti-hIL-5 Ralpha Ab on eosinophil apoptosis in normal subjects. Furthermore, the expression of B-cell lymphoma-2 (Bcl-2) proteins was significantly inhibited by the anti-hIL-5 Ralpha Ab or antisense IL-5 oligonucleotides in asthmatics (p<0.05, n=8), but there was no significant change in eosinophils from normal subjects. This study demonstrates that eosinophils from asthmatics release IL-5 in an autocrine fashion to act on their own IL-5 receptors in prevention of apoptosis through the upregulation of Bcl-2 expression.

Adult↗
PubMed2001

Oncogenic Ras-induced proliferation requires autocrine fibroblast growth factor 2 signaling in skeletal muscle cells.

Constitutively activated Ras proteins are associated with a large number of human cancers, including those originating from skeletal muscle tissue. In this study, we show that ectopic expression of oncogenic Ras stimulates proliferation of the MM14 skeletal muscle satellite cell line in the absence of exogenously added fibroblast growth factors (FGFs). MM14 cells express FGF-1, -2, -6, and -7 and produce FGF protein, yet they are dependent on exogenously supplied FGFs to both maintain proliferation and repress terminal differentiation. Thus, the FGFs produced by these cells are either inaccessible or inactive, since the endogenous FGFs elicit no detectable biological response. Oncogenic Ras-induced proliferation is abolished by addition of an anti-FGF-2 blocking antibody, suramin, or treatment with either sodium chlorate or heparitinase, demonstrating an autocrine requirement for FGF-2. Oncogenic Ras does not appear to alter cellular export rates of FGF-2, which does not possess an NH(2)-terminal or internal signal peptide. However, oncogenic Ras does appear to be involved in releasing or activating inactive, extracellularly sequestered FGF-2. Surprisingly, inhibiting the autocrine FGF-2 required for proliferation has no effect on oncogenic Ras-mediated repression of muscle-specific gene expression. We conclude that oncogenic Ras-induced proliferation of skeletal muscle cells is mediated via a unique and novel mechanism that is distinct from Ras-induced repression of terminal differentiation and involves activation of extracellularly localized, inactive FGF-2.

Animals↗
PubMed2003

Autocrine laminin-5 ligates alpha6beta4 integrin and activates RAC and NFkappaB to mediate anchorage-independent survival of mammary tumors.

Invasive carcinomas survive and evade apoptosis despite the absence of an exogenous basement membrane. How epithelial tumors acquire anchorage independence for survival remains poorly defined. Epithelial tumors often secrete abundant amounts of the extracellular matrix protein laminin 5 (LM-5) and frequently express alpha6beta4 integrin. Here, we show that autocrine LM-5 mediates anchorage-independent survival in breast tumors through ligation of a wild-type, but not a cytoplasmic tail-truncated alpha6beta4 integrin. alpha6beta4 integrin does not mediate tumor survival through activation of ERK or AKT. Instead, the cytoplasmic tail of beta4 integrin is necessary for basal and epidermal growth factor-induced RAC activity, and RAC mediates tumor survival. Indeed, a constitutively active RAC sustains the viability of mammary tumors lacking functional beta1 and beta4 integrin through activation of NFkappaB, and overexpression of NFkappaB p65 mediates anchorage-independent survival of nonmalignant mammary epithelial cells. Therefore, epithelial tumors could survive in the absence of exogenous basement membrane through autocrine LM-5-alpha6beta4 integrin-RAC-NFkappaB signaling.

Autocrine Communication↗
PubMed2001

Hepatopoietin acts as an autocrine growth factor in hepatoma cells.

Hepatopoietin (HPO) is a novel human hepatotrophic factor. Its known function is mainly limited to supporting liver regeneration. Recently, it was shown by our laboratory that HPO acts as a mitogen for hepatoma cell lines and that there are HPO-specific receptors on the surface of these cells (Wang, G., et al., J Biol Chem 1999;274:11469-11472), indicating that HPO might be involved in oncogenesis in the liver. To study this hypothesis, we first conducted experiments in vitro to identify the existence of an autocrine loop of HPO/HPO receptor in hepatoma cell lines. It was demonstrated that HPO was actually expressed by hepatoma cells, such as HepG2, Bel 7402, and SMMC-7721, and secreted into the culture medium. Furthermore, it was shown that HPO-neutralizing antibody has an inhibitory effect on the uptake of tritiated thymidine by hepatoma cells. The results strongly suggest that HPO acts as an autocrine factor for hepatoma cells in vitro.

Aged↗