Nox4 mediates TGF-β1-induced retinoblastoma protein phosphorylation, proliferation, and hypertrophy in human airway smooth muscle cells

2007 ◽  
Vol 292 (6) ◽  
pp. L1543-L1555 ◽  
Author(s):  
Anne Sturrock ◽  
Thomas P. Huecksteadt ◽  
Kimberly Norman ◽  
Karl Sanders ◽  
Thomas M. Murphy ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Smooth Muscle ◽  
Protein Phosphorylation ◽  
Airway Smooth Muscle ◽  
Retinoblastoma Protein ◽  
Airway Smooth Muscle Cells ◽  
Oxygen Species ◽  
Human Airway Smooth Muscle ◽  
Human Airway ◽  
Tgf Β1

Transforming growth factor-β1 (TGF-β1) plays a pivotal role in increasing airway smooth muscle mass in severe asthma by inducing proliferation and hypertrophy of human airway smooth muscle. The mechanism(s) for these effects of TGF-β1 have not been fully elucidated. In this study, we demonstrate that TGF-β1 is a potent inducer of expression of the nonphagocyte NAD(P)H oxidase catalytic homolog Nox4, diphenylene iodonium-inhibitable reactive oxygen species production, proliferation, and hypertrophy in cultured human airway smooth muscle cells. By confocal microscopy, TGF-β1-induced Nox4 was localized with the endoplasmic reticulum and the nucleus, implying a role for Nox4 in regulation of both the cell cycle and protein synthesis. Consistent with this hypothesis, TGF-β1 increased retinoblastoma protein phosphorylation at both Ser807/811 and Ser780. Silencing Nox4 prevented TGF-β1-mediated retinoblastoma protein phosphorylation, proliferation, and cell hypertrophy. TGF-β1 also increased phosphorylation of eukaryotic translation initiation factor 4E binding protein-1 at Thr37/46, and this was likewise blocked by silencing Nox4. This is the first report to suggest a functional role for Nox4 in cell cycle transition and to demonstrate that Nox4 influences the pathobiochemistry of asthma by generating reactive oxygen species that promote TGF-β1-induced proliferation and hypertrophy of human airway smooth muscle.

TGF-β1 stimulates IL-8 release, COX-2 expression, and PGE2release in human airway smooth muscle cells

2000 ◽  
Vol 279 (1) ◽  
pp. L201-L207 ◽  
Author(s):  
Choong Yi Fong ◽  
Linhua Pang ◽  
Elaine Holland ◽  
Alan J. Knox
Keyword(s):  
Smooth Muscle ◽  
Airway Smooth Muscle ◽  
Transforming Growth Factor ◽  
Airway Smooth Muscle Cells ◽  
Dependent Manner ◽  
Human Airway Smooth Muscle ◽  
Human Airway ◽  
Cox Inhibitor ◽  
Cox 2 ◽  
Tgf Β1

We have recently shown that endogenous prostanoids are critical in bradykinin-stimulated interleukin (IL)-8 release from human airway smooth muscle (ASM) cells. In this study, we tested the ability of transforming growth factor (TGF)-β1 to stimulate IL-8 release, cyclooxygenase (COX)-2 expression and PGE2 generation in cultured human ASM cells and explored the role of COX products and COX-2 induction on IL-8 release. TGF-β1 stimulated IL-8 release, COX-2 induction, and PGE2 generation in a concentration- and time-dependent manner. Maximal IL-8 release was achieved with 10 ng/ml of TGF-β1 after 16 h of incubation, which was inhibited by the transcription inhibitor actinomycin D and the corticosteroid dexamethasone but was not affected by the nonselective COX inhibitor indomethacin and the selective COX-2 inhibitor NS-398 despite their inhibition on TGF-β1-induced PGE2 release. These results show for the first time that TGF-β1 stimulates IL-8 release, COX-2 induction, and PGE2 generation in human ASM cells and that PGE2 generation is not critical for TGF-β1-induced IL-8 release. These findings suggest that TGF-β1 may play an important role in the pathophysiology of asthma.

scholarly journals IGFBP-3 mediates TGF-β1-induced cell growth in human airway smooth muscle cells

2000 ◽  
Vol 278 (3) ◽  
pp. L545-L551 ◽  
Author(s):  
Pinchas Cohen ◽  
Roopmathy Rajah ◽  
Joel Rosenbloom ◽  
David J. Herrick
Keyword(s):  
Smooth Muscle ◽  
Growth Factor ◽  
Cell Growth ◽  
Airway Smooth Muscle ◽  
Transforming Growth Factor ◽  
Airway Smooth Muscle Cells ◽  
Human Airway Smooth Muscle ◽  
Human Airway ◽  
Tgf Β1 ◽  
Igfbp 3

Both insulin-like growth factor binding protein-3 (IGFBP-3) and transforming growth factor-β (TGF-β) have been separately shown to have cell-specific growth-inhibiting or growth-potentiating effects. TGF-β stimulates IGFBP-3 mRNA and peptide expression in several cell types, and TGF-β-induced growth inhibition and apoptosis have been shown to be mediated through the induction of IGFBP-3. However, a link between the growth stimulatory effects of TGF-β and IGFBP-3-induction has not been shown. In this study, we investigated the role of IGFBP-3 in mediating TGF-β1-induced cell growth using human airway smooth muscle (ASM) cells as our model. TGF-β1 (1 ng/ml) treatment induced a 10- to 20-fold increase in the levels of expression of IGFBP-3 mRNA and protein. Addition of either IGFBP-3 or TGF-β1 to the growth medium resulted in an approximately twofold increase in cell proliferation. Coincubation of ASM cells with IGFBP-3 antisense (but not sense) oligomers as well as with an IGFBP-3 neutralizing antibody (but not with control IgG) blocked the growth induced by TGF-β1 ( P < 0.001). Several IGFBP-3-associated proteins were observed in ASM cell lysates, which may have a role in the cellular responses to IGFBP-3. These findings demonstrate that IGFBP-3 is capable of mediating the growth stimulatory effect of TGF-β in ASM cells.

scholarly journals Dexamethasone rescues TGF-β1-mediated β2-adrenergic receptor dysfunction and attenuates phosphodiesterase 4D expression in human airway smooth muscle cells

2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Elena Chung ◽  
Christie A. Ojiaku ◽  
Gaoyuan Cao ◽  
Vishal Parikh ◽  
Brian Deeney ◽  
...  
Keyword(s):  
Gene Expression ◽  
Smooth Muscle ◽  
Airway Smooth Muscle ◽  
Adrenergic Receptor ◽  
Airway Smooth Muscle Cells ◽  
Human Airway Smooth Muscle ◽  
Human Airway ◽  
Phosphodiesterase 4D ◽  
Camp Levels ◽  
Tgf Β1

Abstract Glucocorticoids (GCs) and β2-adrenergic receptor (β2AR) agonists improve asthma outcomes in most patients. GCs also modulate gene expression in human airway smooth muscle (HASM), thereby attenuating airway inflammation and airway hyperresponsiveness that define asthma. Our previous studies showed that the pro-fibrotic cytokine, transforming growth factor- β1 (TGF-β1) increases phosphodiesterase 4D (PDE4D) expression that attenuates agonist-induced levels of intracellular cAMP. Decreased cAMP levels then diminishes β2 agonist-induced airway relaxation. In the current study, we investigated whether glucocorticoids reverse TGF-β1-effects on β2-agonist-induced bronchodilation and modulate pde4d gene expression in HASM. Dexamethasone (DEX) reversed TGF-β1 effects on cAMP levels induced by isoproterenol (ISO). TGF-β1 also attenuated G protein-dependent responses to cholera toxin (CTX), a Gαs stimulator downstream from the β2AR receptor. Previously, we demonstrated that TGF-β1 treatment increased β2AR phosphorylation to induce hyporesponsiveness to a β2 agonist. Our current data shows that expression of grk2/3, kinases associated with attenuation of β2AR function, are not altered with TGF-β1 stimulation. Interestingly, DEX also attenuated TGF-β1-induced pde4d gene expression. These data suggest that steroids may be an effective therapy for treatment of asthma patients whose disease is primarily driven by elevated TGF-β1 levels.

A human airway smooth muscle cell line that retains physiological responsiveness

1989 ◽  
Vol 256 (2) ◽  
pp. C329-C335 ◽  
Author(s):  
R. A. Panettieri ◽  
R. K. Murray ◽  
L. R. DePalo ◽  
P. A. Yadvish ◽  
M. I. Kotlikoff
Keyword(s):  
Smooth Muscle ◽  
Cell Line ◽  
Airway Smooth Muscle ◽  
Cytosolic Calcium ◽  
Airway Smooth Muscle Cell ◽  
Airway Smooth Muscle Cells ◽  
Functional Coupling ◽  
Functional Responses ◽  
Human Airway Smooth Muscle ◽  
Human Airway

We report the development of a nontransformed line of human airway smooth muscle cells retaining smooth muscle-specific contractile protein expression and physiological responsiveness to agonists implicated in inflammatory airway diseases. Specific responses to histamine, leukotrienes, bradykinin, platelet-activating factor, substance P, and thromboxane analogues are demonstrated as well as functional coupling to beta-adrenergic receptors. The cell line was characterized using indirect immunofluorescence, as well as electrophoretic separation and immunoblot analysis of smooth muscle-specific actin. Functional responses were assessed by measurements of cytosolic calcium and stimulation of adenosine 3',5'-cyclic monophosphate production. The cells retain their responsiveness over many population doublings and should be a useful model to examine specific receptor-effector mechanisms, as well as the effects of neurohumoral agents on the regulation of airway smooth muscle growth and differentiation.

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