TGF-β Suppresses EGF-Induced MAPK Signaling and Proliferation in Asthmatic Epithelial Cells

Semlali, Abdelhabib; Jacques, Éric; Plante, Sophie; Biardel, Sabrina; Milot, Julie; Laviolette, Michel; Boulet, Louis‐Philippe; Chakir, Jamila

doi:10.1165/rcmb.2007-0031oc

Cited by 47 publications

(40 citation statements)

References 32 publications

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“…These data indicated that TGF-␤1 was not a proliferative stimulus for HBECs in the current treatment period. These results are consistent with the report by Semlali et al (40) that TGF-␤1 does not affect baseline proliferation in asthmatic and nonasthmatic HBECs.…”

Section: Discussionsupporting

confidence: 93%

Differential deposition of fibronectin by asthmatic bronchial epithelial cells

Zeng

Tjin

et al. 2015

American Journal of Physiology-Lung Cellular and Molecular Phys

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Altered ECM protein deposition is a feature in asthmatic airways. Fibronectin (Fn), an ECM protein produced by human bronchial epithelial cells (HBECs), is increased in asthmatic airways. This study investigated the regulation of Fn production in asthmatic or nonasthmatic HBECs and whether Fn modulated HBEC proliferation and inflammatory mediator secretion. The signaling pathways underlying transforming growth factor (TGF)-β1-regulated Fn production were examined using specific inhibitors for ERK, JNK, p38 MAPK, phosphatidylinositol 3 kinase, and activin-like kinase 5 (ALK5). Asthmatic HBECs deposited higher levels of Fn in the ECM than nonasthmatic cells under basal conditions, whereas cells from the two groups had similar levels of Fn mRNA and soluble Fn. TGF-β1 increased mRNA levels and ECM and soluble forms of Fn but decreased cell proliferation in both cells. The rate of increase in Fn mRNA was higher in nonasthmatic cells. However, the excessive amounts of ECM Fn deposited by asthmatic cells after TGF-β1 stimulation persisted compared with nonasthmatic cells. Inhibition of ALK5 completely prevented TGF-β1-induced Fn deposition. Importantly, ECM Fn increased HBEC proliferation and IL-6 release, decreased PGE2 secretion, but had no effect on VEGF release. Soluble Fn had no effect on cell proliferation and inflammatory mediator release. Asthmatic HBECs are intrinsically primed to produce more ECM Fn, which when deposited into the ECM, is capable of driving remodeling and inflammation. The increased airway Fn may be one of the key driving factors in the persistence of asthma and represents a novel, therapeutic target.

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Section: Discussionsupporting

confidence: 93%

Differential deposition of fibronectin by asthmatic bronchial epithelial cells

Zeng

Tjin

et al. 2015

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…In addition, TGF␤ can modulate transcription of immediate early genes in a process mediated by EGFR trans-activation and ERK phosphorylation (41,73). Therefore, we addressed the question of whether morphine treatment attenuated TGF␤-induced TSP1 levels.…”

Section: Discussionmentioning

confidence: 99%

Morphine Modulation of Thrombospondin Levels in Astrocytes and Its Implications for Neurite Outgrowth and Synapse Formation

Ikeda

Miyatake

Koshikawa

et al. 2010

Journal of Biological Chemistry

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Opioid receptor signaling via EGF receptor (EGFR) transactivation and ERK/MAPK phosphorylation initiates diverse cellular responses that are cell type-dependent. In astrocytes, multiple opioid receptor-mediated mechanisms of ERK activation exist that are temporally distinctive and feature different outcomes. Upon discovering that chronic opiate treatment of rats down-regulates thrombospondin 1 (TSP1) expression in the nucleus accumbens and cortex, we investigated the mechanism of action of this modulation in astrocytes. TSP1 is synthesized in astrocytes and is released into the extracellular matrix where it is known to play a role in synapse formation and neurite outgrowth. Acute morphine (hours) reduced TSP1 levels in astrocytes. Chronic (days) opioids repressed TSP1 gene expression and reduced its protein levels by opioid receptor and ERK-dependent mechanisms in astrocytes. Morphine also depleted TSP1 levels stimulated by TGF␤1 and abolished ERK activation induced by this factor. Chronic morphine treatment of astrocyte-neuron co-cultures reduced neurite outgrowth and synapse formation. Therefore, inhibitory actions of morphine were detected after both acute and chronic treatments. An acute mechanism of morphine signaling to ERK that entails depletion of TSP1 levels was suggested by inhibition of morphine activation of ERK by a function-blocking TSP1 antibody. This raises the novel possibility that acute morphine uses TSP1 as a source of EGF-like ligands to activate EGFR. Chronic morphine inhibition of TSP1 is reminiscent of the negative effect of opioids on EGFR-induced astrocyte proliferation via a phospho-ERK feedback inhibition mechanism. Both of these variations of classical EGFR transactivation may enable opiates to diminish neurite outgrowth and synapse formation.Astrocytes are the source of a diverse group of molecules that are required for synapse formation, function, and maintenance in neurons (1-7). Thrombospondin (TSP) 3 is a member of the astrocyte-derived intercellular signaling components that have been implicated in synaptogenesis and other neuronal glial interactions of the developing brain (8 -17). In addition, synaptic plasticity and other neuroadaptations involving astrocyte neuron interactions are thought to play a role in reward learning and addiction (18). Some chronic morphine-responsive genes (Homer1, PSD-95, and synaptotagmin1) may subserve the long lived neuronal and behavioral plasticity observed in regions of the mesolimbic reward system, and they are involved in synaptogenesis (19 -26).TSPs are multidomain, multimeric glycoproteins that are secreted into the extracellular matrix of many cells and serve as bridging molecules in cell-cell interactions (27,28). First discovered in platelet ␣-granules and secreted upon platelet activation, the superfamily of TSPs modulate varied functions of cell signaling and cell adhesion in a broad array of cell types. The five TSP genes are expressed in the CNS and peripheral nervous system where they play important roles in neural development. T...

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“…23,24 Near-confluent epithelial cells from asthmatic patients and control subjects were detached and cultured in 6-well plates. Cells were cultured in 1% FBS-supplemented medium for 24 hours before experiments.…”

Section: Epithelial Cell Culturementioning

confidence: 99%

“…24 DNA was amplified by means of quantitative PCR, as previously described. 25 TSLPR was amplified by using the following primers: 59-GAGTGGCAGTCCAAA CAGGAA-39 as sense and 59-ACATCCTCCATAGCCTTCACC-39 as antisense.…”

Section: Real-time Rt-pcr Analysismentioning

confidence: 99%