Oncostatin M causes VEGF release from human airway smooth muscle: synergy with IL-1β

Vascular endothelial growth factor (VEGF), a potent angiogenesis factor, likely contributes to airway remodeling in asthma. We sought to examine the effects and mechanism of action of IL-6 family cytokines on VEGF release from human airway smooth muscle (HASM) cells. Oncostatin M (OSM), but not other IL-6 family cytokines, increased VEGF release, and IL-1β enhanced OSM-induced VEGF release. OSM increased VEGF mRNA expression and VEGF promoter activity, whereas IL-1β had no effect. IL-1β did not augment the effects of OSM on VEGF promoter activity but did augment OSM-induced VEGF mRNA expression and mRNA stability. The STAT3 inhibitor piceatannol decreased both OSM-induced VEGF release and synergy between OSM and IL-1β, without affecting responses to IL-1β alone. Piceatannol also inhibited OSM-induced VEGF mRNA expression. In contrast, inhibitors of MAPK pathway had no effect on OSM or OSM plus IL-1β-induced VEGF release. OSM increased type 1 IL-1 receptor (IL-1R1) mRNA expression, as measured by real-time PCR, and piceatannol attenuated this response. Consistent with the increase in IL-1R1 expression, OSM markedly augmented IL-1β-induced VEGF, MCP-1, and IL-6 release. In summary, our data indicate OSM causes VEGF expression in HASM cells by a transcriptional mechanism involving STAT3. IL-1β also synergizes with OSM to increase VEGF release, likely as a result of effects of IL-1β on VEGF mRNA stability as well as effects of OSM on IL-1R1 expression. This is the first description of a role for OSM on IL-1R1 expression in any cell type. OSM may contribute to airway remodeling observed in chronic airway disease.

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Adenosine upregulates VEGF expression in cultured myocardial vascular smooth muscle cells

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1999.277.2.h595 ◽

1999 ◽

Vol 277 (2) ◽

pp. H595-H602 ◽

Cited By ~ 10

Author(s):

Jian-Wei Gu ◽

Ann L. Brady ◽

Vivek Anand ◽

Michael C. Moore ◽

Whitney C. Kelly ◽

...

Keyword(s):

Smooth Muscle ◽

Smooth Muscle Cells ◽

Mrna Expression ◽

Vascular Smooth Muscle Cells ◽

Vegf Expression ◽

Vegf Mrna ◽

Protein Levels ◽

Hypoxic Conditions ◽

Vegf Mrna Expression ◽

Vegf Protein

We tested whether adenosine has differential effects on vascular endothelial growth factor (VEGF) expression under normoxic and hypoxic conditions, and whether A1 or A2 receptors (A1R; A2R) mediate these effects. Myocardial vascular smooth muscle cells (MVSMCs) from dog coronary artery were exposed to hypoxia (1% O2) or normoxia (20% O2) in the absence and presence of adenosine agonists or antagonists for 18 h. VEGF protein levels were measured in media with ELISA. VEGF mRNA expression was determined with Northern blot analysis. Under normoxic conditions, the adenosine A1R agonists, N 6-cyclopentyladenosine and R(-)- N 6-(2-phenylisopropyl)adenosine did not increase VEGF protein levels at A1R stimulatory concentrations. However, adenosine (5 μM) and the adenosine A2R agonist N 6-[2-(3,5-dimethoxyphenyl)-2-(2-methylphenyl)]ethyl adenosine (DPMA; 100 nM) increased VEGF protein levels by 51 and 132% and increased VEGF mRNA expression by 44 and 90%, respectively, in cultured MVSMCs under normoxic conditions. Hypoxia caused an approximately fourfold increase in VEGF protein and mRNA expression, which could not be augmented with exogenous adenosine, A2R agonist (DPMA), or A1R agonist [1,3-diethyl-8-phenylxanthine (DPX)]. The A2R antagonist 8-(3-chlorostyryl)-caffeine completely blocked adenosine-induced VEGF protein and mRNA expression and decreased baseline VEGF protein levels by up to ∼60% under normoxic conditions but only by ∼25% under hypoxic conditions. The A1R antagonist DPX had no effect. These results are consistent with the hypothesis that 1) adenosine increases VEGF protein and mRNA expression by way of A2R. 2) Adenosine plays a major role as an autocrine factor regulating VEGF expression during normoxic conditions but has a relatively minor role during hypoxic conditions. 3) Endogenous adenosine can account for the majority of basal VEGF secretion by MVSMCs under normoxic conditions and could therefore be a maintenance factor for the vasculature.

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Urokinase potentiates PDGF-induced chemotaxis of human airway smooth muscle cells

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00092.2002 ◽

2003 ◽

Vol 284 (6) ◽

pp. L1020-L1026 ◽

Cited By ~ 34

Author(s):

Stephen M. Carlin ◽

Michael Roth ◽

Judith L. Black

Keyword(s):

Smooth Muscle ◽

Smooth Muscle Cells ◽

Airway Smooth Muscle ◽

Kinase Inhibitor ◽

Airway Remodeling ◽

Muscle Cells ◽

Mek Inhibitor ◽

Airway Smooth Muscle Cells ◽

Human Airway Smooth Muscle ◽

Human Airway

We investigated the chemotactic action of PDGF and urokinase on human airway smooth muscle (HASM) cells in culture. Cells were put in collagen-coated transwells with 8-μm perforations, incubated for 4 h with test compounds, then fixed, stained, and counted as migrated nuclei by microscopy. Cells from all culture conditions showed some basal migration (migration in the absence of stimuli during the assay), but cells preincubated for 24 h in 10% FBS or 20 ng/ml PDGF showed higher basal migration than cells quiesced in 1% FBS. PDGFBB, PDGFAA, and PDGFABwere all chemotactic when added during the assay. PDGF chemotaxis was blocked by the phosphatidyl 3′-kinase inhibitor LY-294002, the MEK inhibitor U-0126, PGE2, formoterol, pertussis toxin, and the Rho kinase inhibitor Y-27632. Urokinase alone had no stimulatory effect on migration of quiescent cells but caused a dose-dependent potentiation of chemotaxis toward PDGF. Urokinase also potentiated the elevated basal migration of cells pretreated in 10% FBS or PDGF. This potentiating effect of urokinase appears to be novel. We conclude that PDGF and similar cytokines may be important factors in airway remodeling by redistribution of smooth muscle cells during inflammation and that urokinase may be important in potentiating the response.

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Vascular endothelial growth factor (VEGF) mRNA expression in human tumor models of different histologies

Annals of Oncology ◽

10.1093/oxfordjournals.annonc.a059322 ◽

1995 ◽

Vol 6 (8) ◽

pp. 817-825 ◽

Cited By ~ 55

Author(s):

D.P. Berger ◽

L. Herbstritt ◽

W.A. Dengler ◽

D. Marmé ◽

R. Mertelsmann ◽

...

Keyword(s):

Vascular Endothelial Growth Factor ◽

Growth Factor ◽

Mrna Expression ◽

Human Tumor ◽

Vascular Endothelial ◽

Tumor Models ◽

Vegf Mrna ◽

Endothelial Growth Factor ◽

Vegf Mrna Expression

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Interleukin-6 family cytokines: signaling and effects in human airway smooth muscle cells

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.2001.280.6.l1225 ◽

2001 ◽

Vol 280 (6) ◽

pp. L1225-L1232 ◽

Cited By ~ 24

Author(s):

Thomas Lahiri ◽

Johanne D. Laporte ◽

Paul E. Moore ◽

Reynold A. Panettieri ◽

Stephanie A. Shore

Keyword(s):

Smooth Muscle ◽

Airway Smooth Muscle ◽

Cell Types ◽

Oncostatin M ◽

Airway Smooth Muscle Cells ◽

Human Airway Smooth Muscle ◽

Human Airway ◽

Cox 2 ◽

Transcription 3 ◽

Dose Dependent

Interleukin (IL)-1β induces cyclooxygenase (COX)-2 expression and prostanoid formation in cultured human airway smooth muscle (HASM) cells. In other cell types, IL-6 family cytokines induce COX-2 or augment IL-1β-induced COX-2 expression. The purpose of this study was to determine whether IL-6 family cytokines were involved in COX-2 expression in HASM cells. RT-PCR was used to demonstrate that the necessary receptor components for IL-6-type cytokine binding are expressed in HASM cells. IL-6 and oncostatin M (OSM) each caused a dose-dependent phosphorylation of signal transducer and activator of transcription-3, whereas IL-11 did not. IL-6, IL-11, and OSM alone had no effect on COX-2 expression. However, OSM caused dose-dependent augmentation of COX-2 expression and prostaglandin (PG) E2release induced by IL-1β. In contrast, IL-6 and IL-11 did not alter IL-1β-induced COX-2 expression. IL-6 did increase IL-1β-induced PGE2formation in unstimulated cells but not in cells stimulated with arachidonic acid (AA; 10−5M), suggesting that IL-6 effects were mediated at the level of AA release. Our results indicate that IL-6 and OSM are capable of inducing signaling in HASM cells. In addition, OSM and IL-1β synergistically cause COX-2 expression and PGE2release.

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Oncostatin M promotes biphasic tissue factor expression in smooth muscle cells: evidence for Erk-1/2 activation

Blood ◽

10.1182/blood.v97.3.692 ◽

2001 ◽

Vol 97 (3) ◽

pp. 692-699 ◽

Cited By ~ 34

Author(s):

Toshiya Nishibe ◽

Graham Parry ◽

Atsushi Ishida ◽

Salim Aziz ◽

Jacqueline Murray ◽

...

Keyword(s):

Smooth Muscle ◽

Dna Binding ◽

Smooth Muscle Cells ◽

Mrna Expression ◽

Tissue Factor ◽

Muscle Cells ◽

Binding Activity ◽

Oncostatin M ◽

Dna Binding Activity ◽

Atherosclerotic Lesions

Abstract Tissue factor (TF), a transmembrane glycoprotein, initiates the extrinsic coagulation cascade. TF is known to play a major role in mediating thrombosis and thrombotic episodes associated with the progression of atherosclerosis. Macrophages at inflammatory sites, such as atherosclerotic lesions, release numerous cytokines that are capable of modulating TF expression. This study examined the role of oncostatin M (OSM), a macrophage/ T-lymphocyte–restricted cytokine, in the expression of TF in vascular smooth muscle cells (SMCs). It is reported here that OSM stimulated a biphasic and sustained pattern of TF messenger RNA (mRNA). The effect of OSM on TF mRNA expression was regulated at the transcriptional level as determined by nuclear run-offs and transient transfection of a TF promoter-reporter gene construct. OSM-induced TF expression was regulated primarily by the transcription factor NF-κB. Activation of NF-κB by OSM did not require IκB-α degradation. Inhibition of MEK activity by U0126 prevented OSM-induced TF expression by suppressing NF-κB DNA binding activity as determined by gel-shift analysis. Further, inhibition of Erk-1/2 protein by antisense treatment resulted in suppression of TF mRNA expression, indicating a role for Erk-1/2 in modulating NF-κB DNA binding activity. These studies suggest that the induced expression of TF by OSM is primarily through the activation of NF-κB and that activation of NF-κB is regulated in part by the MEK/Erk-1/2 signal transduction pathway. This study indicates that OSM may play a key role in promoting TF expression in SMCs within atherosclerotic lesions.

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