The Proprotein Convertase Furin inhibits IL-13 Induced Inflammation in Airway Smooth Muscle by Regulating Integrin Associated Signaling Complexes

2021 ◽  
Author(s):  
Yidi Wu ◽  
Youliang Huang ◽  
Wenwu Zhang ◽  
Susan J. Gunst
Keyword(s):  
Smooth Muscle ◽  
Airway Smooth Muscle ◽  
Inflammatory Responses ◽  
Therapeutic Potential ◽  
Proprotein Convertase ◽  
Akt Activation ◽  
Inflammatory Conditions ◽  
Muscle Tissues ◽  
Muscle Myosin

Furin is a proprotein convertase that regulates the activation and inactivation of multiple proteins including matrix metalloproteinases, integrins and cytokines. It is a serine endoprotease that localizes to the plasma membrane and can be secreted into the extracellular space. The role of furin in regulating inflammation in isolated canine airway smooth muscle tissues was investigated. The treatment of airway tissues with recombinant furin (rFurin) inhibited the activation of Akt and eotaxin secretion induced by IL-13, and it prevented the IL-13 induced suppression of smooth muscle myosin heavy chain expression. rFurin promoted a differentiated phenotype by activating β1 integrin proteins and stimulating the activation of the adhesome proteins vinculin and paxillin by talin. Activated paxillin induced the binding of Akt to β-parvin IPP (ILK, PINCH, parvin) complexes, which inhibits Akt activation. Treatment of tissues with a furin inhibitor or the depletion of endogenous furin using shRNA resulted in Akt activation and inflammatory responses similar to those induced by IL-13. Furin inactivation or IL-13 caused talin cleavage and integrin inactivation, resulting in the inactivation of vinculin and paxillin. Paxillin inactivation resulted in the coupling of Akt to α-parvin IPP complexes, which catalyze Akt activation and an inflammatory response. The results demonstrate that furin inhibits inflammation in airway smooth muscle induced by IL-13, and that the anti-inflammatory effects of furin are mediated by activating integrin proteins and integrin-associated signaling complexes that regulate Akt-mediated pathways to the nucleus. Furin may have therapeutic potential for the treatment of inflammatory conditions of the lungs and airways.

scholarly journals Mechanical stimuli and IL-13 interact at integrin adhesion complexes to regulate expression of smooth muscle myosin heavy chain in airway smooth muscle tissue

2011 ◽  
Vol 301 (3) ◽  
pp. L275-L284 ◽  
Author(s):  
Leena P. Desai ◽  
Yidi Wu ◽  
Robert S. Tepper ◽  
Susan J. Gunst
Keyword(s):  
Smooth Muscle ◽  
Protein Expression ◽  
Airway Smooth Muscle ◽  
Heavy Chain ◽  
High Load ◽  
Phenotypic Marker ◽  
Akt Activation ◽  
Muscle Tissues ◽  
Low Load ◽  
Muscle Myosin

Airway smooth muscle phenotype may be modulated in response to external stimuli under physiological and pathophysiological conditions. The effect of mechanical forces on airway smooth muscle phenotype were evaluated in vitro by suspending weights of 0.5 or 1 g from the ends of canine tracheal smooth muscle tissues, incubating the weighted tissues for 6 h, and then measuring the expression of the phenotypic marker protein, smooth muscle myosin heavy chain (SmMHC). Incubation of the tissues at a high load significantly increased expression of SmMHC compared with incubation at low load. Incubation of the tissues at a high load also decreased activation of PKB/Akt, as indicated by its phosphorylation at Ser 473. Inhibition of Akt or phosphatidylinositol-3,4,5 triphosphate-kinase increased SmMHC expression in tissues at low load but did not affect SmMHC expression at high load. IL-13 induced a significant increase in Akt activation and suppressed the expression of SmMHC protein at both low and high loads. The role of integrin signaling in mechanotransduction was evaluated by expressing a PINCH (LIM1–2) fragment in the muscle tissues that prevents the membrane localization of the integrin-binding IPP complex (ILK/PINCH/α-parvin), and also by expressing an inactive integrin-linked kinase mutant (ILK S343A) that inhibits endogenous ILK activity. Both mutants inhibited Akt activation and increased expression of SmMHC protein at low load but had no effect at high load. These results suggest that mechanical stress and IL-13 both act through an integrin-mediated signaling pathway to oppositely regulate the expression of phenotypic marker proteins in intact airway smooth muscle tissues. The stimulatory effects of mechanical stress on contractile protein expression oppose the suppression of contractile protein expression mediated by IL-13; thus the imposition of mechanical strain may inhibit changes in airway smooth muscle phenotype induced by inflammatory mediators.

scholarly journals Focal adhesion kinase (FAK) and mechanical stimulation negatively regulate the transition of airway smooth muscle tissues to a synthetic phenotype

2016 ◽  
Vol 311 (5) ◽  
pp. L893-L902 ◽  
Author(s):  
Yidi Wu ◽  
Youliang Huang ◽  
Susan J. Gunst
Keyword(s):  
Smooth Muscle ◽  
Focal Adhesion Kinase ◽  
Airway Smooth Muscle ◽  
Focal Adhesion ◽  
Inflammatory Responses ◽  
Mechanical Load ◽  
Akt Activation ◽  
Lower Load ◽  
Synthetic Phenotype

The effects of mechanical forces and focal adhesion kinase (FAK) in regulating the inflammatory responses of airway smooth muscle (ASM) tissues to stimulation with interleukin (IL)-13 were investigated. Canine tracheal tissues were subjected to different mechanical loads in vitro, and the effects of mechanical load on eotaxin secretion and inflammatory signaling pathways in response to IL-13 were determined. Eotaxin secretion by tissues in response to IL-13 was significantly inhibited in muscles maintained at a higher (+) load compared with those at a lower (−) load as assessed by ELISA, and Akt activation was also reduced in the higher (+) loaded tissues. Conversely the (+) mechanical load increased activation of the focal adhesion proteins FAK and paxillin in the tissues. The role of FAK in regulating the mechanosensitive responses was assessed by overexpressing FAK-related nonkinase in the tissues, by expressing the FAK kinase-dead mutant FAK Y397F, or by treating tissues with the FAK inhibitor PF-573228. FAK inactivation potentiated Akt activity and increased eotaxin secretion in response to IL-13. FAK inhibition also suppressed the mechanosensitivity of Akt activation and eotaxin secretion. In addition, FAK inactivation suppressed smooth muscle myosin heavy chain expression induced by the higher (+) mechanical load. The results demonstrate that the imposition of a higher mechanical load on airway smooth muscle stimulates FAK activation, which promotes the expression of the differentiated contractile phenotype and suppresses the synthetic phenotype and the inflammatory responses of the muscle tissue.

Role for TAK1 in cigarette smoke-induced proinflammatory signaling and IL-8 release by human airway smooth muscle cells

2012 ◽  
Vol 303 (3) ◽  
pp. L272-L278 ◽  
Author(s):  
Tonio Pera ◽  
Claudia Atmaj ◽  
Marieke van der Vegt ◽  
Andrew J. Halayko ◽  
Johan Zaagsma ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Map Kinase ◽  
Cigarette Smoke ◽  
Airway Smooth Muscle ◽  
Transforming Growth Factor ◽  
Inflammatory Responses ◽  
Dominant Negative ◽  
Airflow Limitation ◽  
Airway Smooth Muscle Cells

Chronic obstructive pulmonary disease (COPD) is an inflammatory disease, characterized by a progressive decline in lung function. Airway smooth muscle (ASM) mass may be increased in COPD, contributing to airflow limitation and proinflammatory cytokine production. Cigarette smoke (CS), the major risk factor of COPD, causes ASM cell proliferation, as well as interleukin-8 (IL-8)-induced neutrophilia. In various cell types, transforming growth factor-β-activated kinase 1 (TAK1) plays a crucial role in MAP kinase and NF-κB activation, as well as IL-8 release induced by IL-1β, TNF-α, and lipopolysaccharide. The role of TAK1 in CS-induced IL-8 release is not known. The aim of this study was to investigate the role of TAK1 in CS-induced NF-κB and MAP kinase signaling and IL-8 release by human ASM cells. Stimulation of these cells with CS extract (CSE) increased IL-8 release and ERK-1/2 phosphorylation, as well as Iκ-Bα degradation and p65 NF-κB subunit phosphorylation. CSE-induced ERK-1/2 phosphorylation and Iκ-Bα degradation were both inhibited by pretreatment with the specific TAK1 inhibitor LL-Z-1640-2 (5Z-7-oxozeaenol; 100 nM). Similarly, expression of dominant-negative TAK1 inhibited CSE-induced ERK-1/2 phosphorylation. In addition, inhibitors of TAK1 and the NF-κB (SC-514; 50 μM) and ERK-1/2 (U-0126; 3 μM) signaling inhibited the CSE-induced IL-8 release by ASM cells. These data indicate that TAK1 plays a major role in CSE-induced ERK-1/2 and NF-κB signaling and in IL-8 release by human ASM cells. Furthermore, they identify TAK1 as a novel target for the inhibition of CS-induced inflammatory responses involved in the development and progression of COPD.

scholarly journals A-kinase-anchoring proteins coordinate inflammatory responses to cigarette smoke in airway smooth muscle

2015 ◽  
Vol 308 (8) ◽  
pp. L766-L775 ◽  
Author(s):  
Wilfred J. Poppinga ◽  
Irene H. Heijink ◽  
Laura J. Holtzer ◽  
Philipp Skroblin ◽  
Enno Klussmann ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Cigarette Smoke ◽  
Airway Smooth Muscle ◽  
Lung Tissue ◽  
Inflammatory Responses ◽  
Camp Signaling ◽  
Chronic Obstructive ◽  
Mrna Levels ◽  
Anchoring Proteins

β2-Agonist inhibitors can relieve chronic obstructive pulmonary disease (COPD) symptoms by stimulating cyclic AMP (cAMP) signaling. A-kinase-anchoring proteins (AKAPs) compartmentalize cAMP signaling by establishing protein complexes. We previously reported that the β2-agonist fenoterol, direct activation of protein kinase A (PKA), and exchange factor directly activated by cAMP decrease cigarette smoke extract (CSE)-induced release of neutrophil attractant interleukin-8 (IL-8) from human airway smooth muscle (ASM) cells. In the present study, we tested the role of AKAPs in CSE-induced IL-8 release from ASM cells and assessed the effect of CSE on the expression levels of different AKAPs. We also studied mRNA and protein expression of AKAPs in lung tissue from patients with COPD. Our data show that CSE exposure of ASM cells decreases AKAP5 and AKAP12, both capable of interacting with β2-adrenoceptors. In lung tissue of patients with COPD, mRNA levels of AKAP5 and AKAP12 were decreased compared with lung tissue from controls. Using immunohistochemistry, we detected less AKAP5 protein in ASM of patients with COPD Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage II compared with control subjects. St-Ht31, which disrupts AKAP-PKA interactions, augmented CSE-induced IL-8 release from ASM cells and diminished its suppression by fenoterol, an effect mediated by disturbed ERK signaling. The modulatory role of AKAP-PKA interactions in the anti-inflammatory effects of fenoterol in ASM cells and the decrease in expression of AKAP5 and AKAP12 in response to cigarette smoke and in lungs of patients with COPD suggest that cigarette smoke-induced changes in AKAP5 and AKAP12 in patients with COPD may affect efficacy of pharmacotherapy.

GRO-α regulation in airway smooth muscle by IL-1β and TNF-α: role of NF-κB and MAP kinases

2006 ◽  
Vol 291 (1) ◽  
pp. L66-L74 ◽  
Author(s):  
Razao Issa ◽  
Shaoping Xie ◽  
Kang-Yun Lee ◽  
Rex D. Stanbridge ◽  
Pankaj Bhavsar ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Mrna Expression ◽  
Airway Smooth Muscle ◽  
Map Kinases ◽  
Inflammatory Responses ◽  
Airway Smooth Muscle Cells ◽  
Dependent Manner ◽  
Tnf Α ◽  
Inflammatory Chemokines

Airway smooth muscle cells (ASMC) are a source of inflammatory chemokines that may propagate airway inflammatory responses. We investigated the production of the CXC chemokine growth-related oncogene protein-α (GRO-α) from ASMC induced by cytokines and the role of MAPK and NF-κB pathways. ASMC were cultured from human airways, grown to confluence, and exposed to cytokines IL-1β and TNF-α after growth arrest. GRO-α release, measured by ELISA, was increased by >50-fold after IL-1β (0.1 ng/ml) or 5-fold after TNF-α (1 ng/ml) in a dose- and time-dependent manner. GRO-α release was not affected by the T helper type 2 cytokines IL-4, IL-10, and IL-13. IL-1β and TNF-α also induced GRO-α mRNA expression. Supernatants from IL-1β-stimulated ASMC were chemotactic for neutrophils; this effect was inhibited by anti-GRO-α blocking antibody. AS-602868, an inhibitor of IKK-2, and PD-98059, an inhibitor of ERK, inhibited GRO-α release and mRNA expression, whereas SP-600125, an inhibitor of JNK, reduced GRO-α release without effect on mRNA expression. SB-203580, an inhibitor of p38 MAPK, had no effect. AS-602868 but not PD-98059 or SP-600125 inhibited p65 DNA-binding induced by IL-1β and TNF-α. By chromatin immunoprecipitation assay, IL-1β and TNF-α enhanced p65 binding to the GRO-α promoter, which was inhibited by AS-602868. IL-1β- and TNF-α-stimulated expression of GRO-α from ASMC is regulated by independent pathways involving NF-κB activation and ERK and JNK pathways. GRO-α released from ASMC participates in neutrophil chemotaxis.

scholarly journals The Inflammatory Role of Pro-Resolving Mediators in Endometriosis: An Integrative Review

2021 ◽  
Vol 22 (9) ◽  
pp. 4370
Author(s):  
Cássia de Fáveri ◽  
Paula M. Poeta Fermino ◽  
Anna P. Piovezan ◽  
Lia K. Volpato
Keyword(s):  
Intracellular Signaling ◽  
Inflammatory Responses ◽  
Therapeutic Potential ◽  
Critical Role ◽  
Integrative Review ◽  
Inflammatory Factors ◽  
Resolvin D1 ◽  
Endogenous Factors

The pathogenesis of endometriosis is still controversial, although it is known that the inflammatory immune response plays a critical role in this process. The resolution of inflammation is an active process where the activation of endogenous factors allows the host tissue to maintain homeostasis. The mechanisms by which pro-resolving mediators (PRM) act in endometriosis are still little explored. Thus, this integrative review aims to synthesize the available content regarding the role of PRM in endometriosis. Experimental and in vitro studies with Lipoxin A4 demonstrate a potential inhibitory effect on endometrial lesions’ progression, attenuating pro-inflammatory and angiogenic signals, inhibiting proliferative and invasive action suppressing intracellular signaling induced by cytokines and estradiol, mainly through the FPR2/ALX. Investigations with Resolvin D1 demonstrated the inhibition of endometrial lesions and decreased pro-inflammatory factors. Annexin A1 is expressed in the endometrium and is specifically present in women with endometriosis, although the available studies are still inconsistent. Thus, we believe there is a gap in knowledge regarding the PRM pathways in patients with endometriosis. It is important to note that these substances’ therapeutic potential is evident since the immune and abnormal inflammatory responses play an essential role in endometriosis development and progression.

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