Neurotensin Decreases the Proinflammatory Status of Human Skin Fibroblasts and Increases Epidermal Growth Factor Expression

Published on Aug 11, 2014in International Journal of Inflammation
· DOI :10.1155/2014/248240
Lucília P. da Silva14
Estimated H-index: 14
(UC: University of Coimbra),
Bruno Miguel Neves18
Estimated H-index: 18
(UC: University of Coimbra)
+ 2 AuthorsEugenia Carvalho34
Estimated H-index: 34
(UC: University of Coimbra)
Fibroblasts colonization into injured areas during wound healing (WH) is responsible for skin remodelling and is also involved in the modulation of inflammation, as fibroblasts are immunologically active. Herein, we aimed to determine neurotensin effect on the immunomodulatory profile of fibroblasts, both in homeostatic and inflammatory conditions. Neurotensin mediated responses occurred through NTR1 or NTR3 receptors, while under inflammatory conditions NTR1 expression increase seemed to modulate neurotensin responses. Among different immunomodulatory genes, CCL11, IL-8, and IL-6 were the most expressed genes, while CCL4 and EGF were the less expressed genes. After neurotensin exposure, IL-8 mRNA expression was increased while CCL11 was decreased, suggesting a proinflammatory upregulation and chemoattractant ability downregulation of fibroblasts. Under inflammatory conditions, gene expression was significantly increased. After neurotensin exposure, CCL4 and IL-6 mRNA expression were decreased while CCL11 was increased, suggesting again a decrease in the chemoattractant capacity of fibroblasts and in their proinflammatory status. Furthermore, the expression of EGF, a crucial growth factor for skin cells proliferation and WH, was increased in all conditions. Overall, neurotensin, released by nerve fibers or skin cells, may be involved in the decrease of the chemotaxis and the proinflammatory status in the proliferation and remodelling phases of WH.
📖 Papers frequently viewed together
58 Citations
72 Citations
33 Citations
#1Konstantinos–Dionysios Alysandratos (Tufts University)H-Index: 1
#1Konstantinos-Dionysios Alysandratos (Tufts University)H-Index: 21
Last. Theoharis C. TheoharidesH-Index: 98
view all 8 authors...
Stress affects immunity, but the mechanism is not known. Neurotensin (NT) and corticotropin-releasing hormone (CRH) are secreted under stress in various tissues, and have immunomodulatory actions. We had previously shown that NT augments the ability of CRH to increase mast cell-dependent skin vascular permeability in rodents. Here we show that NT triggered human mast cell degranulation and significantly augmented CRH-induced vascular endothelial growth factor (VEGF) release. Investigation of var...
65 CitationsSource
#1Magdalini Vasiadi (Tufts University)H-Index: 20
#2Anastasia Therianou (Athens State University)H-Index: 8
Last. Theoharis C. TheoharidesH-Index: 98
view all 11 authors...
Psoriasis is a chronic inflammatory skin disorder characterized by keratinocyte hyperproliferation and increased epidermal vascularization, associated with high skin vascular endothelial growth factor (VEGF).1 Neuropeptides have been implicated in psoriasis,2 but their mechanism of action is not well understood. Neurotensin (NT), is a vasoactive peptide,3 which increases histamine release from rodent skin in a mast cell-dependent manner.4 NT also augments the effect of corticotrophin-releasing h...
21 CitationsSource
#1Ana TellecheaH-Index: 14
#2Ermelindo C. LealH-Index: 22
Last. Eugenia Carvalho (UC: University of Coimbra)H-Index: 34
view all 4 authors...
Diabetic foot ulceration (DFU) is one of the most costly and debilitating complications of diabetes and is the leading cause of non-traumatic amputations, affecting 15% of the diabetic population. Impaired wound healing in diabetic patients without large-vessel disease has been attributed to microvascular dysfunction, neuropathy, and abnormal cellular and inflammatory responses. These abnormalities have been examined mainly in animal models although a few studies have been undertaken in diabetic...
27 CitationsSource
#1Theoharis C. Theoharides (Tufts University)H-Index: 98
#2Konstantinos-Dionysios Alysandratos (Tufts University)H-Index: 21
Last. Dimitrios KalogeromitrosH-Index: 19
view all 11 authors...
Mast cells are well known for their role in allergic and anaphylactic reactions, as well as their involvement in acquired and innate immunity. Increasing evidence now implicates mast cells in inflammatory diseases where they are activated by non-allergic triggers, such as neuropeptides and cytokines, often exerting synergistic effects as in the case of IL-33 and neurotensin. Mast cells can also release pro-inflammatory mediators selectively without degranulation. In particular, IL-1 induces sele...
474 CitationsSource
#1Lucília P. da Silva (UC: University of Coimbra)H-Index: 14
#2Bruno Miguel Neves (UC: University of Coimbra)H-Index: 18
Last. Eugenia Carvalho (UC: University of Coimbra)H-Index: 34
view all 5 authors...
In the last decades some reports reveal the neuropeptide neurotensin (NT) as an immune mediator in the Central Nervous System and in the gastrointestinal tract, however its effects on skin immunity were not identified. The present study investigates the effect of NT on signal transduction and on pro/anti-inflammatory function of skin dendritic cells. Furthermore, we investigated how neurotensin can modulate the inflammatory responses triggered by LPS in skin dendritic cells. We observed that fet...
33 CitationsSource
#1David E. Cochrane (Tufts University)H-Index: 17
#2Robert E. Carraway (UMMS: University of Massachusetts Medical School)H-Index: 23
Last. Ross S. Feldberg (Tufts University)H-Index: 15
view all 6 authors...
Objective and design To determine if mast cells synthesize the inflammatory peptide, neurotensin (NT), secrete immunoreactive and bioactive NT, and express the NT receptor NTS1.
11 CitationsSource
#1Lucília P. da Silva (UC: University of Coimbra)H-Index: 14
#2Eugenia Carvalho (UC: University of Coimbra)H-Index: 34
Last. Maria Teresa Cruz (UC: University of Coimbra)H-Index: 31
view all 3 authors...
Importance of the field: In 2010, the world prevalence of diabetes is 6.4%, affecting 285 million adults. Diabetic patients are at risk of developing neuropathy and delayed wound healing that can culminate in incurable diabetic foot ulcerations (DFUs) or even foot amputation.Areas covered in this review: The contrast between cellular and molecular events of wound healing and diabetic wound healing processes is characterized. Neuropeptides released from the autonomous nervous system and skin cell...
58 CitationsSource
Abstract Epidermal keratinocytes are the main component cells of the epidermis and their function is regulated by various kinds of growth factors, cytokines, and chemokines. Of these, members of the epidermal growth factor and fibroblast growth factor families, as wells as hepatocyte growth factor and insulin-like growth factor, play central roles in keratinocyte proliferation, while transforming growth factor-β, vitamin D3, and interferon-γ are important inhibitors of keratinocyte growth. Kerat...
84 CitationsSource
#1Anuja K. Antony (UIC: University of Illinois at Chicago)H-Index: 8
#2Wuyi KongH-Index: 10
Last. H. Peter LorenzH-Index: 41
view all 3 authors...
Scarless fetal skin wound healing is a paradigm for ideal skin repair and is dependent on peripheral nerve function. To further explore neurogenic mechanisms influence on the scarless skin repair, fetal rats were wounded on gestational days 16 (E16; n = 24) and 18 (E18; n = 8) and wounds were harvested at 1 and 3 days after injury. Unwounded skin at identical gestational age was used for control comparison. The scarless E16 and scarring El 8 wounds underwent macroarray gene expression analysis (...
15 CitationsSource
#1Bruno Miguel Neves (UC: University of Coimbra)H-Index: 18
#2Maria Teresa Cruz (UC: University of Coimbra)H-Index: 31
Last. Maria Celeste Lopes (UC: University of Coimbra)H-Index: 29
view all 10 authors...
Dendritic cells (DC) are professional antigen-presenting cells with a unique capacity to initiate and modulate immune responses by their ability to prime naive T-cells. Upon stimuli, DC experience several morphologic, phenotypic and functional changes in a process referred to as maturation. This process is crucial to the biological functions of DC since their maturation status confer them the ability to polarize distinct T-cell subsets. In this work we explored the relevance of PI3-Kinase, Mitog...
55 CitationsSource
Cited By16
#1Marija Petkovic (RU: Roskilde University)
#2Michelle Vang Mouritzen (RU: Roskilde University)H-Index: 4
Last. Håvard Jenssen (RU: Roskilde University)H-Index: 40
view all 0 authors...
Cutaneous wound healing is a vital biological process that aids skin regeneration upon injury. Wound healing failure results from persistent inflammatory conditions observed in diabetes, or autoimmune diseases like psoriasis. Chronic wounds are incurable due to factors like poor oxygenation, aberrant function of peripheral sensory nervature, inadequate nutrients and blood tissue supply. The most significant hallmark of chronic wounds is heavily aberrant immune skin function. The immune response ...
#1Nicole C. Nowak (NU: Northwestern University)
#2Daniela M. Menichella (NU: Northwestern University)H-Index: 13
Last. Amy S. Paller (NU: Northwestern University)H-Index: 36
view all 4 authors...
Type 2 diabetes (T2D) is associated with several potential comorbidities, among them impaired wound healing, chronic ulcerations, and the requirement for lower extremity amputation. Disease-associated abnormal cellular responses, infection, immunological and microvascular dysfunction, and peripheral neuropathy are implicated in the pathogenesis of the wound healing impairment and the diabetic foot ulcer. The skin houses a dense network of sensory nerve afferents and nerve-derived modulators, whi...
#1Michelle Vang Mouritzen (RU: Roskilde University)H-Index: 4
#2Marija Petkovic (UC: University of Coimbra)H-Index: 1
Last. Håvard Jenssen (RU: Roskilde University)H-Index: 40
view all 10 authors...
Abstract Bovine lactoferricin (LFcinB) has antimicrobial and immunomodulatory properties, however, the effects on diabetic wound healing remain poorly understood. The wound healing potential of LFcinB was investigated using in vitro, ex vivo, and in vivo models. Cell migration and proliferation were tested on keratinocytes and on porcine ears. A type 1 diabetic mouse model was also used to evaluate wound healing kinetics, bacterial diversity patterns and the effect of LFcinB on oxidative stress,...
#1Hosna Zare (MUMS: Mashhad University of Medical Sciences)H-Index: 6
#2Majid Rezayi (MUMS: Mashhad University of Medical Sciences)H-Index: 25
Last. Mojtaba Sankian (MUMS: Mashhad University of Medical Sciences)H-Index: 22
view all 9 authors...
Diabetic foot ulcers (DFUs) are chronic severe complications of diabetes disease and remain a worldwide clinical challenge with social and economic consequences. Diabetic wounds can cause infection, amputation of lower extremities, and even death. Several factors including impaired angiogenesis, vascular insufficiency, and bacterial infections result in a delayed process of wound healing in diabetic patients. Treatment of wound infections using traditional antibiotics has become a critical statu...
1 CitationsSource
#1Marija Petkovic (UC: University of Coimbra)H-Index: 1
Last. Louise Torp DalgaardH-Index: 25
view all 5 authors...
Wound healing is a complex biological process that is impaired under diabetes conditions. Chronic non-healing wounds in diabetes are some of the most expensive healthcare expenditures worldwide. Early diagnosis and efficacious treatment strategies are needed. microRNAs (miRNAs), a class of 18–25 nucleotide long RNAs, are important regulatory molecules involved in gene expression regulation and in the repression of translation, controlling protein expression in health and disease. Recently, miRNA...
1 CitationsSource
#1Jing Li (UK: University of Kentucky)H-Index: 35
#1Jing Li (UK: University of Kentucky)H-Index: 31
Last. B. Mark Evers (UK: University of Kentucky)H-Index: 87
view all 13 authors...
We previously reported that high levels of plasma neurotensin (NT), a gut hormone released from enteroendocrine cells of the small bowel, contribute to obesity and comorbid conditions. Gut microbiota has been implicated in the obesity development. Paneth cells are critical in maintaining gut microbiota composition and homeostasis by releasing antimicrobial proteins including alpha-defensins. The purpose of our current study was to determine the possible role of NT in gut microbiota composition a...
2 CitationsSource
#1Ewelina Russjan (PAN: Polish Academy of Sciences)H-Index: 3
#2Katarzyna Kaczyńska (PAN: Polish Academy of Sciences)H-Index: 8
Neurotensin (NT) demonstrates ambiguous activity on inflammatory processes. The present study was undertaken to test the potential anti-inflammatory activity of NT in a murine model of non-atopic asthma and to establish the contribution of NTR1 receptors. Asthma was induced in BALB/c mice by skin sensitization with dinitrofluorobenzene followed by intratracheal hapten provocation. The mice were treated intraperitoneally with NT, SR 142948 (NTR1 receptor antagonist) + NT or NaCl. Twenty-four hour...
7 CitationsSource
#1Camila Nunes Lemos (USP: University of São Paulo)H-Index: 5
#2Camila Cubayachi (USP: University of São Paulo)H-Index: 5
Last. Renata Fonseca Vianna Lopez (USP: University of São Paulo)H-Index: 29
view all 7 authors...
Abstract Silk fibroin (SF) films containing a peptide, neurotensin (NT), stimulated by iontophoresis were developed aiming to modulate the inflammatory process and prevent the growth of microorganisms typical of wounds. NT-loaded SF films composition shows predominance of β-sheet structures that conferred adequate mechanical properties, transparency, moderate roughness and low swelling index to fibroin films. Infrared spectroscopy and thermal analysis suggested the presence of non-covalent inter...
12 CitationsSource
#1Michelle Vang Mouritzen (RU: Roskilde University)H-Index: 4
#2Sali Abourayale (RU: Roskilde University)H-Index: 1
Last. Håvard Jenssen (RU: Roskilde University)H-Index: 40
view all 8 authors...
The work was funded by the Danish Council for Independent Research, Technology and Production, grant 4005‐00029; Strategic Project POCI‐01‐0145‐FEDER‐007440 funded by FEDER through Operational Programme Competitiveness Factors, the European Foundation for the Study of Diabetes (Novartis European Research Programme in Microvascular Complications of Diabetes), and FCT; and Pepper grant P30 AG028718 and NIGMS‐NIH P20GM109096 to EC.
8 CitationsSource
#1Zhifang Zheng (Southern Medical University)H-Index: 3
#2Yishu Liu (Third Military Medical University)H-Index: 3
Last. Biao Cheng (Third Military Medical University)H-Index: 5
view all 7 authors...
AbstractDiabetic foot ulcers (DFUs) are a threat to human health and can lead to amputation and even death. Recently neurotensin (NT), an inflammatory modulator in wound healing, was found to be beneficial for diabetic wound healing. As we demonstrated previously, polylactide–polyglycolide (PLGA) and cellulose nanocrystals (CNCs) (PLGA/CNC) nanofiber membranes show good cytocompatibility and facilitate fibroblast adhesion, spreading and proliferation. PLGA/CNC nanofiber membranes are novel mater...
10 CitationsSource