Fibroblasts support migration of monocyte‐derived dendritic cells by secretion of <scp>PGE</scp><sub>2</sub> and <scp>MMP</scp>‐1

Saalbach, Anja; Janik, Tobias; Busch, M.; Herbert, Diana; Anderegg, Ulf; Simon, Jan C.

doi:10.1111/exd.12722

Cited by 20 publications

(16 citation statements)

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“…COX-2 and its downstream products have been implicated in promoting cell migration in a variety of cell types [15–17]. To determine whether TNF-α-induced COX-2 expression was involved in myofibroblast migration, 18Co cells were first exposed to TNF-α (10 ng/ml) over 4 h and COX-2 expression was analyzed by Western blot.…”

Section: Resultsmentioning

confidence: 99%

“…COX-2 is a known downstream target of TNF-α in colonic myofibroblasts [1, 4, 18, 25], is up-regulated in the setting of intestinal inflammation [26, 27], and regulates cell migration in a number of cell types [15–17]. Having demonstrated that TNF-α stimulates COX-2 expression in a P38 MAPK-dependent manner, we sought to determine whether COX-2 was involved in TNF-α-mediated myofibroblast migration.…”

Section: Resultsmentioning

confidence: 99%

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TNF-α stimulates colonic myofibroblast migration via COX-2 and Hsp27

Saini

Liu

Yoo

2016

Journal of Surgical Research

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Backround Crohn’s disease (CD) is a chronic inflammatory enteropathy characterized by fibrotic strictures. Myofibroblasts (MFB) are stromal cells of the GI tract found in increased numbers in patients with CD and represent the key effector cells involved in pathologic fibrosis. MFB are a known target of TNF-α, a pro-inflammatory cytokine strongly implicated in the pathophysiology of CD. However, the precise mechanisms through which TNF-α contributes to fibrosis remain incompletely understood. Here, we demonstrate for the first time that TNF-α increases MFB migration through the COX-2 and Hsp27 pathways. Materials and Methods The human colonic MFB cell line 18Co was grown to confluence on 35×10mm cell culture dishes and used from passages 8–14. An in vitro scratch assay assessed the effect of TNF-α (10 ng/ml) on MFB migration over 24 hours in the presence or absence of several inhibitors (NS398, SB203580, Hsp27 siRNA). Results TNF-α significantly increased MFB migration over 24 h. TNF-α also led to the increased expression of COX-2 and stimulated rapid phosphorylation of Hsp27 at Ser-82. TNF-α-induced-COX-2 expression, Hsp27 phosphorylation, and MFB migration were all significantly inhibited by the P38 MAPK inhibitor SB203580 (p<0.05). TNF-α-induced MFB migration was also significantly inhibited by NS398 (p<0.05), a direct inhibitor of COX-2, and by siRNA targeting Hsp27 (p<0.05). Conclusions TNF-α stimulates colonic myofibroblast migration through P38 MAPK-mediated activation of COX-2 and Hsp27. Further elucidating these inflammatory signaling pathways may lead to novel therapeutic targets for the treatment of Crohn’s disease related fibrosis and strictures.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

TNF-α stimulates colonic myofibroblast migration via COX-2 and Hsp27

Saini

Liu

Yoo

2016

Journal of Surgical Research

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“…Human MoDCs were generated from CD14‐positive monocytes from whole blood using CD14 + Cell Isolation Kit (Miltenyi, Bergisch Gladbach, Germany) according to manufacturer's instructions. Monocytes were cultivated in DC medium as described .…”

Section: Methodsmentioning

confidence: 99%

Free fatty acids sensitize dendritic cells to amplify TH1/TH17‐immune responses

et al. 2016

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Obesity is associated with body fat gain and impaired glucose metabolism. Here, we identified both body fat gain in obesity and impaired glucose metabolism as two independent risk factors for increased serum levels of free fatty acids (FFAs). Since obesity is associated with increased and/or delayed resolution of inflammation observed in various chronic inflammatory diseases such as psoriasis, we investigated the impact of FFAs on human monocyte-derived and mouse bone marrow-derived dendritic cell (DCs) functions relevant for the pathogenesis of chronic inflammation. FFAs such as palmitic acid (PA) and oleic acid (OA) did not affect the pro-inflammatory immune response of DCs. In contrast, PA and OA sensitize DCs resulting in augmented secretion of TH1/TH17-instructive cytokines upon pro-inflammatory stimulation. Interestingly, obesity in mice worsened a TH1/TH17-driven psoriasis-like skin inflammation. Strong correlation of the amount of total FFA, PA, and OA in serum with the severity of skin inflammation points to a critical role of FFA in obesity-mediated exacerbation of skin inflammation. Our data suggest that increased levels of FFAs might be a predisposing factor promoting a TH1/TH17-mediated inflammation such as psoriasis in response to an inflammatory danger signal.Keywords: Dendritic cells r Diet r Free fatty acids r Inflammation r Metabolism r TH1 r TH17 Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionHuman and mouse studies demonstrate that immune responses are dysregulated in obesity. In particular, obesity in mice is associated with increased inflammation and/or its delayed resolution Correspondence: Dr. Anja Saalbach e-mail: Anja. Saalbach@medizin.uni-leipzig.de in models of acute pancreatitis, arthritis, and neutrophil-mediated peritonitis [1][2][3][4]. Kanemaru et al. described a worsening of psoriasis from dermatitis in mice by upregulating IL-17A, IL-22, and Reg3c in skin [5]. Likewise human psoriasis, a chronic TH1/TH17-driven inflammatory skin disease, shows a significant positive * These authors contributed equally to this work. Eur. J. Immunol. 2016Immunol. . 46: 2043Immunol. -2053 correlation between body mass index (BMI) and the onset and severity of the disease as well as a weaker response to treatment [6,7]. Obesity is associated with low-grade chronic inflammation reflected by increased levels of acute-phase proteins and pro-inflammatory mediators as well as by a pro-inflammatory state of circulating mononuclear cells in obese compared to lean subjects [3,8]. Enlarged adipocytes change their secretion pattern and release more pro-inflammatory mediators such as TNF-α and MCP-1, while the release of anti-inflammatory mediators such as adiponectin is reduced [9][10][11]. Thus, white adipose tissue could link metabolism and inflammation [12]. Moreover, in obesity, visceral adipose tissues as well as subcutaneous fat depots enlarge and adipocyte production of free fatty acids (FFAs), mainly palmitic acid (PA)...

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“…Furthermore, in cervical lesions, PGE 2 expression is higher compared with in normal tissues (9)(10)(11). Additionally, certain studies have revealed that PGE 2 modulates the migration of DCs (12,13). Therefore, PGE 2 may be associated with changes in DCs in cervical lesions.…”

Section: Introductionmentioning

confidence: 99%

E6‑regulated overproduction of prostaglandin�E2 may inhibit migration of dendritic cells in human papillomavirus 16‑positive cervical lesions

et al. 2020

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Continuous human papillomavirus (HPV) infection is a critical cause of cervical lesions; however, the specific mechanism is currently not clear. E6 is one of the most important oncoproteins associated with HPV, which regulates synthases in the production of prostaglandin E2 (PGE 2 ). Notably, PGE 2 has been reported to be upregulated in cervical lesions. An insufficient number of mature dendritic cells (DCs), which is unable to cause an effective immune response, is an important cause of cervical lesions. Therefore, this study explored the possible causes of HPV16-positive cervical lesions by identifying the relationship between E6, PGE 2 and DCs. Firstly, the distribution and status of DCs in clinical biopsy specimens and animal models were analyzed with immunohistochemistry and flow cytometry, which demonstrated that the migratory ability of DCs was inhibited in HPV16-positive cervical lesions. Furthermore, using immunohistochemistry, western blotting and ELISA, it was revealed that as the degree of cervical lesions increased, the expression of PGE 2 and its synthases increased. Subsequently, as determined using Transwell and 3D migration assays, it was revealed that a high concentration of PGE 2 inhibited the migration of DCs, which may explain the phenomenon observed in cervical lesions. Notably, E6 was identified to regulate PGE 2 expression. The in vivo experiments indicated that E6 may increase the expression levels of PGE 2 in cervical lesions, which could eventually induce inhibition of the migration of DCs. In conclusion, the present study suggested that E6 regulated overproduction of PGE 2 , which may induce inhibition of DC migration in HPV16-positive cervical lesions.

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Fibroblasts support migration of monocyte‐derived dendritic cells by secretion of PGE₂ and MMP‐1

Cited by 20 publications

References 50 publications

TNF-α stimulates colonic myofibroblast migration via COX-2 and Hsp27

TNF-α stimulates colonic myofibroblast migration via COX-2 and Hsp27

Free fatty acids sensitize dendritic cells to amplify TH1/TH17‐immune responses

E6‑regulated overproduction of prostaglandin�E2 may inhibit migration of dendritic cells in human papillomavirus 16‑positive cervical lesions

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Fibroblasts support migration of monocyte‐derived dendritic cells by secretion of PGE2 and MMP‐1

Cited by 20 publications

References 50 publications

TNF-α stimulates colonic myofibroblast migration via COX-2 and Hsp27

TNF-α stimulates colonic myofibroblast migration via COX-2 and Hsp27

Free fatty acids sensitize dendritic cells to amplify TH1/TH17‐immune responses

E6‑regulated overproduction of prostaglandin�E2 may inhibit migration of dendritic cells in human papillomavirus 16‑positive cervical lesions

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Fibroblasts support migration of monocyte‐derived dendritic cells by secretion of PGE₂ and MMP‐1