Chronic inflammation enhances NGF-β/TrkA system expression via EGFR/MEK/ERK pathway activation in Sjögren’s syndrome

Lisi, Sabrina; Sisto, Margherita; Ribatti, Doménico; D'Amore, Mario; Lucro, Raffella De; Frassanito, Maria Antonia; Lorusso, Loredana; Vacca, Angelo; Lofrumento, Dario Domenico

doi:10.1007/s00109-014-1130-9

Cited by 15 publications

(11 citation statements)

References 63 publications

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“…Estrogen has favorable effects on reducing pain, 18,28,29 but no certain mechanisms have been identified. From others' work, we knew that ERK was involved in the NGF upstream 42 and downstream 33 pathways. So we investigated the role of MEK-ERK in chondrocyte NGF metabolism.…”

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confidence: 99%

Estrogen Regulation of the Expression of Pain Factor NGF in Rat Chondrocytes

Shang¹,

Zhang²,

Jin³

et al. 2021

JPR

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Objective: Pain is the main symptom of osteoarthritis (OA). Nerve growth factor (NGF) plays a crucial role in the generation of OA pain. And estrogen-alone used resulted in a sustained joint pain reduction in postmenopausal women. So we aim to find whether estrogen alters chondrocytes' NGF level, affecting OA pain. Methods: Primary chondrocytes and cartilage explants isolated from Sprague Dawley rat knees were cultured with physiological concentrations of estrogen (17β-Estradiol ≥ 98%, E2), Estrogen Receptor α (ERα) inhibitor and stimulants. Then, chondrocytes NGF mRNA expression and protein release were analyzed by a quantitative real-time polymerase chain reaction (qPCR) and enzyme-linked immunosorbent assay (ELISA) respectively. Additionally, cultures were pre-incubated with MEK-ERK inhibitor to identify the signaling pathway that estrogen alters NGF mRNA and protein levels. Results: We found that chondrocytes NGF expression and release were decreased by E2. E2 also reduced chondrocytes IL-1β-stimulated or TGF-β1-stimulated NGF expression. Phosphorylated extracellular signal-regulated kinasep1/2 (p-ERK1/2) signals were detected stronger than the control group by Western Blotting (WB). When we cultured chondrocytes with PD98059 (MEK-ERK inhibitor, PD), NGF mRNA expression was added to 1.41Ct (2.07±0.1 fold). Conclusion:We showed that E2 reduces chondrocytes NGF expression significantly, even after stimulation by TGF-β1 or IL-1β. MEK-ERK signaling is involved in this process.

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confidence: 99%

Estrogen Regulation of the Expression of Pain Factor NGF in Rat Chondrocytes

Shang¹,

Zhang²,

Jin³

et al. 2021

JPR

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“…pSS glandular lymphocytic infiltrate contains T and B cells, which in association with resident epithelial cells, generate a proinflammatory microenvironment containing IL-1, IL-6, TNF-α and IFN-γ 16 , 17 among other cytokines 25 – 27 , a number of chemokines 18 , 19 , as well as growth factors, such as nerve growth factor-β 28 . It has been suggested that the mechanism for gland destruction in pSS is the apoptosis of ductal cells.…”

Section: Discussionmentioning

confidence: 99%

Functional effects of proinflammatory factors present in Sjögren’s syndrome salivary microenvironment in an in vitro model of human salivary gland

Arce-Franco

Domínguez-Luis

Pec

et al. 2017

Sci Rep

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Primary Sjögren’s syndrome (pSS) is an autoimmune exocrinopathy in which the role that the immune response plays in reducing exocrine gland function, including the glandular microenvironment of cytokines, has not been fully understood. Epithelial cells from biopsies of human parotid gland (HPG) were used to establish a model of human salivary gland in vitro. In this model, the functional consequences of several proinflammatory soluble factors present in the pSS glandular microenvironment were assessed. Stimulation with isoproterenol and calcium produced a significant increase in the basal activity of amylase in the HPG cell supernatants. Under these conditions, the presence of TNF-α and CXCL12 increased amylase mRNA cellular abundance, but reduced the amylase activity in the cell-free supernatant in a dose-dependent manner. IL-1β and IFN-γ, but not TGF-β, also diminished amylase secretion by HPG cells. These results suggest that the glandular microenvironment of cytokine, by acting post-transcriptionally, may be responsible, at least in part, for the reduced exocrine function observed in pSS patients. These data may help to a better understanding of the pathogenesis of SS, which in turn would facilitate the identification of new therapeutic targets for this disorder.

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“…For this reason, on the basis of clinical observation, pSS was defined as an "autoimmune epithelitis" [12]. Indeed, SGEC are capable of releasing many cytokines that result overexpressed and thus act as key molecules in chronic inflammation, contributing to both systemic and exocrine manifestations of pSS [13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29]. A number of explanations has been offered for the dysregulated cytokine network in pSS and, in the past, the presence of anti-Ro/SSA and anti-La/SSB antibodies was shown to be related to increased glandular and extra-glandular manifestations.…”

Section: Sjögren's Syndromementioning

confidence: 99%

Understanding the Complexity of Sjögren’s Syndrome: Remarkable Progress in Elucidating NF-κB Mechanisms

Sisto

Ribatti

Lisi

2020

JCM

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Sjögren’s syndrome (SS) is a systemic autoimmune inflammatory disease with a poorly defined aetiology, which targets exocrine glands (particularly salivary and lachrymal glands), affecting the secretory function. Patients suffering from SS exhibit persistent xerostomia and keratoconjunctivitis sicca. It is now widely acknowledged that a chronic grade of inflammation plays a central role in the initiation, progression, and development of SS. Consistent with its key role in organizing inflammatory responses, numerous recent studies have shown involvement of the transcription factor nuclear factor κ (kappa)-light-chain-enhancer of activated B cells (NF-κB) in the development of this disease. Therefore, chronic inflammation is considered as a critical factor in the disease aetiology, offering hope for the development of new drugs for treatment. The purpose of this review is to describe the current knowledge about the NF-κB-mediated molecular events implicated in the pathogenesis of SS.

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Chronic inflammation enhances NGF-β/TrkA system expression via EGFR/MEK/ERK pathway activation in Sjögren’s syndrome

Abstract: NGF-β and TrkA expression is elevated in salivary gland epithelial cells of primary Sjögren's syndrome (pSS). Overexpression of NGF-β/TrkA system in pSS occurs via EGFR/Raf-1/MEK/ERK pathway. In pSS, NGF-β overexpression was prevented by EGFR/Raf-1/MEK/ERK pathway inhibition.

Cited by 15 publications

References 63 publications

Estrogen Regulation of the Expression of Pain Factor NGF in Rat Chondrocytes

Estrogen Regulation of the Expression of Pain Factor NGF in Rat Chondrocytes

Functional effects of proinflammatory factors present in Sjögren’s syndrome salivary microenvironment in an in vitro model of human salivary gland

Understanding the Complexity of Sjögren’s Syndrome: Remarkable Progress in Elucidating NF-κB Mechanisms

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