The Proprotein Convertase Furin Suppresses the Inflammatory Responses of Airway Smooth Muscle (ASM) Tissues to IL-13 by Modulating Integrin-Mediated Signaling Pathways

2019 ◽  
Author(s):  
W. Zhang ◽  
Y. Wu ◽  
Y. Huang ◽  
S.J. Gunst
Keyword(s):  
Smooth Muscle ◽  
Signaling Pathways ◽  
Airway Smooth Muscle ◽  
Inflammatory Responses ◽  
Proprotein Convertase

TLR2 ligand engagement upregulates airway smooth muscle TNFα-induced cytokine production

2012 ◽  
Vol 302 (9) ◽  
pp. L838-L845 ◽  
Author(s):  
Melanie Manetsch ◽  
Petra Seidel ◽  
Udo Heintz ◽  
Wenchi Che ◽  
J. Margaret Hughes ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Signaling Pathways ◽  
Airway Smooth Muscle ◽  
Inflammatory Responses ◽  
Respiratory Infections ◽  
Mapk Signaling ◽  
Chronic Obstructive ◽  
Tlr2 Expression ◽  
Chronic Airway

Airway inflammation and respiratory infections are important factors contributing to disease exacerbation in chronic airway diseases such as asthma and chronic obstructive pulmonary disease. Airway smooth muscle (ASM) cells express Toll-like receptors (TLRs) and may be involved in the amplification of airway inflammatory responses during infectious exacerbations. We determined whether infectious stimuli (mimicked using Pam3CSK4, a synthetic bacterial lipopeptide that binds to TLR2/TLR1) further enhance ASM cell inflammatory responses to TNFα in vitro and the signaling pathways involved. Human ASM cells were pretreated for 1 h with Pam3CSK4 (1 μg/ml) in the absence or presence of TNFα (10 ng/ml), and IL-6 and IL-8 release was measured after 24 h. As expected, stimulation with Pam3CSK4 or TNFα alone induced significant IL-6 and IL-8 release. Furthermore, Pam3CSK4 significantly increased TNFα-induced IL-6 and IL-8 mRNA expression and protein release and neutrophil chemotactic activity. The potentiating effect of Pam3CSK4 on TNFα-induced inflammatory responses was not due to enhanced TLR2 expression nor did it involve augmentation of NF-κB or MAPK signaling pathways. Rather, Pam3CSK4 induced cAMP response element (CRE) binding protein phosphorylation and induced CRE-mediated transcriptional regulation, suggesting that Pam3CSK4 and TNFα are acting in concert to enhance ASM cytokine secretion via parallel transcriptional pathways. Our findings suggest that ASM cells may be involved in the amplification of airway inflammatory responses during infectious exacerbations in chronic airway disease.

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 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.

Airway smooth muscle excitation-contraction coupling and airway hyperresponsiveness

2005 ◽  
Vol 83 (8-9) ◽  
pp. 725-732 ◽  
Author(s):  
Simon Hirota ◽  
Peter B Helli ◽  
Adriana Catalli ◽  
Allyson Chew ◽  
Luke J Janssen
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Signaling Pathways ◽  
Airway Smooth Muscle ◽  
Airway Hyperresponsiveness ◽  
Rho Kinase ◽  
Shortness Of Breath ◽  
Excitation Contraction Coupling ◽  
Contraction Coupling ◽  
Hallmark Feature

The primary complaints from patients with asthma pertain to function of airway smooth muscle (ASM) function including shortness of breath, wheezing, and coughing. Thus, it is imperative to better understand the mechanisms underlying excitation-contraction coupling in ASM. Here, we review the various signaling pathways underlying contraction in ASM, and then examine how these are altered in asthma and airway hyperresponsiveness (a hallmark feature of asthma). Throughout, we highlight how studies of vascular smooth muscle have helped or hindered progress in understanding ASM physiology and pathophysiology.Key words: airway smooth muscle, vascular smooth muscle, excitation-contraction coupling, calcium, Rho-kinase.

scholarly journals TGF-β regulates Nox4, MnSOD and catalase expression, and IL-6 release in airway smooth muscle cells

2011 ◽  
Vol 300 (2) ◽  
pp. L295-L304 ◽  
Author(s):  
Charalambos Michaeloudes ◽  
Maria B. Sukkar ◽  
Nadia M. Khorasani ◽  
Pankaj K. Bhavsar ◽  
Kian Fan Chung
Keyword(s):  
Smooth Muscle ◽  
Antioxidant Enzymes ◽  
Airway Smooth Muscle ◽  
Manganese Superoxide Dismutase ◽  
Redox Regulation ◽  
Transforming Growth Factor ◽  
Inflammatory Responses ◽  
Chronic Obstructive ◽  
Airway Smooth Muscle Cells ◽  
Nadph Oxidase 4

Reactive oxygen species (ROS) are generated as a result of normal cellular metabolism, mainly through the mitochondria and peroxisomes, but their release is enhanced by the activation of oxidant enzymes such as NADPH oxidases or downregulation of endogenous antioxidant enzymes such as manganese-superoxide dismutase (MnSOD) and catalase. Transforming growth factor-β (TGF-β), found to be overexpressed in airway smooth muscle (ASM) from asthmatic and chronic obstructive pulmonary disease patients, may be a pivotal regulator of abnormal ASM cell (ASMC) function in these diseases. An important effect of TGF-β on ASMC inflammatory responses is the induction of IL-6 release. TGF-β also triggers intracellular ROS release in ASMCs by upregulation of NADPH oxidase 4 (Nox4). However, the effect of TGF-β on the expression of key antioxidant enzymes and subsequently on oxidant/antioxidant balance is unknown. Moreover, the role of redox-dependent pathways in the mediation of the proinflammatory effects of TGF-β in ASMCs is unclear. In this study, we show that TGF-β induced the expression of Nox4 while at the same time inhibiting the expression of MnSOD and catalase. This change in oxidant/antioxidant enzymes was accompanied by elevated ROS levels and IL-6 release. Further studies revealed a role for Smad3 and phosphatidyl-inositol kinase-mediated pathways in the induction of oxidant/antioxidant imbalance and IL-6 release. The changes in oxidant/antioxidant enzymes and IL-6 release were reversed by the antioxidants N-acetyl-cysteine (NAC) and ebselen through inhibition of Smad3 phosphorylation, indicating redox-dependent activation of Smad3 by TGF-β. Moreover, these findings suggest a potential role for NAC in preventing TGF-β-mediated pro-oxidant and proinflammatory responses in ASMCs. Knockdown of Nox4 using small interfering RNA partially prevented the inhibition of MnSOD but had no effect on catalase and IL-6 expression. These findings provide novel insights into redox regulation of ASM function by TGF-β.

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.

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