scholarly journals ADAM17, A Key Player of Cardiac Inflammation and Fibrosis in Heart Failure Development During Chronic Catecholamine Stress

2021 ◽  
Vol 9 ◽  
Author(s):  
Joseph Adu-Amankwaah ◽  
Gabriel Komla Adzika ◽  
Adebayo Oluwafemi Adekunle ◽  
Marie Louise Ndzie Noah ◽  
Richard Mprah ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Dysfunction ◽  
Limited Information ◽  
Cardiac Inflammation ◽  
Persistent Inflammation ◽  
Extracellular Signal ◽  
Mitogen Activated Protein ◽  
Interleukin 6 Receptor ◽  
Factor Α ◽  
Necrosis Factor

Heart failure development is characterized by persistent inflammation and progressive fibrosis owing to chronic catecholamine stress. In a chronic stress state, elevated catecholamines result in the overstimulation of beta-adrenergic receptors (βARs), specifically β2-AR coupling with Gαi protein. Gαi signaling increases the activation of receptor-stimulated p38 mitogen-activated-protein-kinases (p38 MAPKs) and extracellular signal-regulated kinases (ERKs). Phosphorylation by these kinases is a common way to positively regulate the catalytic activity of A Disintegrin and Metalloprotease 17 (ADAM17), a metalloprotease that has grown much attention in recent years and has emerged as a chief regulatory hub in inflammation, fibrosis, and immunity due to its vital proteolytic activity. ADAM17 cleaves and activates proinflammatory cytokines and fibrotic factors that enhance cardiac dysfunction via inflammation and fibrosis. However, there is limited information on the cardiovascular aspect of ADAM17, especially in heart failure. Hence, this concise review provides a comprehensive insight into the structure of ADAM17, how it is activated and regulated during chronic catecholamine stress in heart failure development. This review highlights the inflammatory and fibrotic roles of ADAM17’s substrates; Tumor Necrosis Factor α (TNFα), soluble interleukin-6 receptor (sIL-6R), and amphiregulin (AREG). Finally, how ADAM17-induced chronic inflammation and progressive fibrosis aggravate cardiac dysfunction is discussed.

scholarly journals Extracellular Signal-regulated Kinase Phosphorylates Tumor Necrosis Factor α-converting Enzyme at Threonine 735: A Potential Role in Regulated Shedding

2002 ◽  
Vol 13 (6) ◽  
pp. 2031-2044 ◽  
Author(s):  
Elena Dı́az-Rodrı́guez ◽  
Juan Carlos Montero ◽  
Azucena Esparı́s-Ogando ◽  
Laura Yuste ◽  
Atanasio Pandiella
Keyword(s):  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Tumor Necrosis Factor Α ◽  
Converting Enzyme ◽  
Erk Activation ◽  
Extracellular Signal Regulated Kinase ◽  
Extracellular Signal ◽  
Mitogen Activated Protein ◽  
Factor Α ◽  
Necrosis Factor

The ectodomain of certain transmembrane proteins can be released by the action of cell surface proteases, termed secretases. Here we have investigated how mitogen-activated protein kinases (MAPKs) control the shedding of membrane proteins. We show that extracellular signal-regulated kinase (Erk) acts as an intermediate in protein kinase C-regulated TrkA cleavage. We report that the cytosolic tail of the tumor necrosis factor α-converting enzyme (TACE) is phosphorylated by Erk at threonine 735. In addition, we show that Erk and TACE associate. This association is favored by Erk activation and by the presence of threonine 735. In contrast to the Erk route, the p38 MAPK was able to stimulate TrkA cleavage in cells devoid of TACE activity, indicating that other proteases are also involved in TrkA shedding. These results demonstrate that secretases are able to discriminate between the different stimuli that trigger membrane protein ectodomain cleavage and indicate that phosphorylation by MAPKs may regulate the proteolytic function of membrane secretases.

scholarly journals Analysis of Mitogen-Activated Protein Kinases in Bone and Cartilage of Patients with Rheumatoid Arthritis Treated with Abatacept

2016 ◽  
Vol 9 ◽  
pp. CMAMD.S34424 ◽  
Author(s):  
Katsuaki Kanbe ◽  
Koei Oh ◽  
Junji Chiba ◽  
Yasuo Inoue ◽  
Masashi Taguchi ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Map Kinases ◽  
Histological Changes ◽  
Extracellular Signal ◽  
Protein Map ◽  
Mitogen Activated Protein ◽  
Hematoxylin And Eosin ◽  
Factor Α ◽  
Necrosis Factor ◽  
And Cartilage

The aim of this study was to analyze the histological changes related to mitogen-activated protein (MAP) kinases in bone and cartilage treated with abatacept for rheumatoid arthritis (RA). A total of 20 patients of bone and cartilage were assessed: 10 abatacept with methotrexate (MTX)-treated RA patients were compared with 10 MTX-treated RA patients (control). The histology of bone and cartilage was observed by staining with hematoxylin and eosin and analyzed immunohistochemically for the expression of tumor necrosis factor-α, interleukin-6, CD4 (T cell), CD68 (macrophage), receptor activator of nuclear kappa-B ligand, osteoprotegerin, osteopontin, CD29 (β-1 integrin), phospho-p38 MAPK (Tyr180/Tyr182), phospho-p44/42 MAPK (extracellular signal-regulated kinase, ERK1/ERK2), and phosphor-c-Jun N-terminal kinase. The expressions of CD29 known as mechanoreceptor and ERK known as mechanotransduction signal protein in MAP kinases in the bone and cartilage of patients treated with abatacept were significantly different from those of control. These findings suggest that increases in CD29 and ERK in MAP kinases may change the metabolism of bone and cartilage in RA patients treated with abatacept.

scholarly journals Chrysin Inhibits TNFα-Induced TSLP Expression through Downregulation of EGR1 Expression in Keratinocytes

2021 ◽  
Vol 22 (9) ◽  
pp. 4350
Author(s):  
Hyunjin Yeo ◽  
Younghan Lee ◽  
Sungshin Ahn ◽  
Euitaek Jung ◽  
Yoongho Lim ◽  
...  
Keyword(s):  
Clinical Symptoms ◽  
Skin Lesions ◽  
Therapeutic Agents ◽  
Mitogen Activated Protein Kinase ◽  
Necrosis Factor Alpha ◽  
Extracellular Signal ◽  
Mitogen Activated Protein ◽  
Signaling Axis ◽  
Factor Alpha ◽  
Necrosis Factor

Thymic stromal lymphopoietin (TSLP) is an epithelial cell-derived cytokine that acts as a critical mediator in the pathogenesis of atopic dermatitis (AD). Various therapeutic agents that prevent TSLP function can efficiently relieve the clinical symptoms of AD. However, the downregulation of TSLP expression by therapeutic agents remains poorly understood. In this study, we investigated the mode of action of chrysin in TSLP suppression in an AD-like inflammatory environment. We observed that the transcription factor early growth response (EGR1) contributed to the tumor necrosis factor alpha (TNFα)-induced transcription of TSLP. Chrysin attenuated TNFα-induced TSLP expression by downregulating EGR1 expression in HaCaT keratinocytes. We also showed that the oral administration of chrysin improved AD-like skin lesions in the ear and neck of BALB/c mice challenged with 2,4-dinitrochlorobenzene. We also showed that chrysin suppressed the expression of EGR1 and TSLP by inhibiting the extracellular signal-regulated kinase (ERK) 1/2 and c-Jun N-terminal kinase (JNK) 1/2 mitogen-activated protein kinase pathways. Collectively, the findings of this study suggest that chrysin improves AD-like skin lesions, at least in part, through the downregulation of the ERK1/2 or JNK1/2-EGR1-TSLP signaling axis in keratinocytes.

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