Immune escape of colorectal tumours via local <scp>LRH</scp>‐1/Cyp11b1‐mediated synthesis of immunosuppressive glucocorticoids

Ahmed, Asma; Reinhold, Cindy; Breunig, Eileen; Phan, Truong San; Dietrich, Lea; Kostadinova, Feodora Ivanova; Urwyler, Corinne; Merk, Verena M.; Noti, Mario; Silva, Israel Toja da; Bode, Konstantin; Nahle, Fatima; Plazzo, Anna Pia; Koerner, Julia; Stuber, Regula; Menche, Constantin; Karamitopoulou, Eva; Farin, Henner F.; Gollob, Kenneth J.; Brunner, Thomas

doi:10.1002/1878-0261.13414

Cited by 7 publications

(5 citation statements)

References 53 publications

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“…The development of novel targeted therapies often benefits from a better understanding of local immune responses in the lungs. Given the well documented role of local GC synthesis in the regulation inflammatory processes in the skin and intestine ( 9 , 15 , 26 ), endogenous GC synthesis in the lung may hold similar promises. It is generally accepted that GC play an important role in the regulation of lung development, and that GC treatment of preterm infants in utero has great therapeutic success in reducing lung disorders such as respiratory distress syndrome (RDS) ( 27 , 28 ).…”

Section: Discussionmentioning

confidence: 99%

Local glucocorticoid synthesis regulates house dust mite-induced airway hypersensitivity in mice

Merk,

Phan,

Wiedmann

et al. 2023

Front. Immunol.

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BackgroundExtra-adrenal glucocorticoid (GC) synthesis at epithelial barriers, such as skin and intestine, has been shown to be important in the local regulation of inflammation. However, the role of local GC synthesis in the lung is less well studied. Based on previous studies and the uncontentious efficacy of corticosteroid therapy in asthma patients, we here investigated the role of 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1/Hsd11b1)-dependent local GC reactivation in the regulation of allergic airway inflammation.MethodsAirway inflammation in Hsd11b1-deficient and C57BL/6 wild type mice was analyzed after injection of lipopolysaccharide (LPS) and anti-CD3 antibody, and in acute and chronic models of airway hypersensitivity induced by house dust mite (HDM) extract. The role of 11β-HSD1 in normal and inflammatory conditions was assessed by high dimensional flow cytometry, histological staining, RT-qPCR analysis, ex vivo tissue cultures, GC-bioassays and protein detection by ELISA and immunoblotting.ResultsHere we show that lung tissue from Hsd11b1-deficient mice synthesized significantly less GC ex vivo compared with wild type animals in response to immune cell stimulation. We further observed a drastically aggravated phenotype in Hsd11b1-deficient mice treated with HDM extract compared to wild type animals. Besides eosinophilic infiltration, Hsd11b1-deficient mice exhibited aggravated neutrophilic infiltration caused by a strong Th17-type immune response.ConclusionWe propose an important role of 11β-HSD1 and local GC in regulating Th17-type rather than Th2-type immune responses in HDM-induced airway hypersensitivity in mice by potentially controlling Toll-like receptor 4 (TLR4) signaling and cytokine/chemokine secretion by airway epithelial cells.

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Section: Discussionmentioning

confidence: 99%

Local glucocorticoid synthesis regulates house dust mite-induced airway hypersensitivity in mice

Merk,

Phan,

Wiedmann

et al. 2023

Front. Immunol.

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“…While they are classically used as anti-inflammation drugs, accumulating evidence has demonstrated that glucocorticoids can also treat malignant tumors such as multiple myeloma [23], prostate cancer [24], colorectal cancer [25] and breast cancer [26]. Inflammation is closely related to the development of most types of cancers.…”

Section: Discussionmentioning

confidence: 99%

Mometasone Furoate Inhibits the Progression of Head and Neck Squamous Cell Carcinoma via Regulating Protein Tyrosine Phosphatase Non-Receptor Type 11

Qiu,

Gao,

Tao

et al. 2023

Biomedicines

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Mometasone furoate (MF) is a kind of glucocorticoid with extensive pharmacological actions, including inhibiting tumor progression; however, the role of MF in head and neck squamous cell carcinoma (HNSCC) is still unclear. This study aimed to evaluate the inhibitory effect of MF against HNSCC and investigate its underlying mechanisms. Cell viability, colony formation, cell cycle and cell apoptosis were analyzed to explore the effect of MF on HNSCC cells. A xenograft study model was used to investigate the effect of MF on HNSCC in vivo. The core targets of MF for HNSCC were identified using network pharmacology analysis, TCGA database analysis and real-time PCR. Molecular docking was performed to determine the binding energy. Protein tyrosine phosphatase non-receptor type 11 (PTPN11)-overexpressing cells were constructed, and then, the cell viability and the expression levels of proliferation- and apoptosis-related proteins were detected after treatment with MF to explore the role of PTPN11 in the inhibitory effect of MF against HNSCC. After cells were treated with MF, cell viability and the number of colonies were decreased, the cell cycle was arrested and cell apoptosis was increased. The xenograft study results showed that MF could inhibit cell proliferation via promoting cell apoptosis in vivo. PTPN11 was shown to be the core target of MF against HNSCC via network pharmacology analysis, TCGA database analysis and real-time PCR. The molecular docking results revealed that PTPN11 exhibited the strongest ability to bind to MF. Finally, MF could attenuate the effects of increased cell viability and decreased cell apoptosis caused by PTPN11 overexpression, suggesting that MF can inhibit the progression of HNSCC by regulating PTPN11. MF targeted PTPN11, promoting cell cycle arrest and cell apoptosis, and consequently exerting effective anti-tumor activity.

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“…Lungs were perfused with phosphate‐buffered saline (PBS) and macroscopically dissected to obtain trachea, main stem bronchi, and lung lobes. Ex vivo organ cultures were performed as previously published 5,8,23,24 . Tissues (10 mg) were cut and cultured in Dulbecco's Modified Eagle Medium (DMEM) (containing 50 μg/mL gentamycin, 2,5 mM L‐glutamine), in the absence or presence of 200 μg/mL metyrapone (MET), 100 μM 11‐dehydrocorticosterone (11‐Dhc) (VWR, Radnor, USA), or 11‐deoxycorticosterone acetate (11‐Doc) (Sigma, St. Louis, USA), and incubated for 16 h (37°C, 5% CO 2 ).…”

Section: Methodsmentioning

confidence: 99%

Glucocorticoids are differentially synthesized along the murine and human respiratory tree

Merk

Renzulli

Vrugt

et al. 2023

Allergy

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BackgroundSynthetic glucocorticoids (GC) are effective in the treatment of inflammatory diseases of the lung. However, long‐term use leads to severe side effects. Endogenous GC can be synthesized locally, either de novo from cholesterol in a 11β‐hydroxylase (Cyp11b1)‐dependent manner, or by reactivation from 11‐dehydrocorticosterone/cortisone by 11β‐hydroxysteroid dehydrogenase 1 (Hsd11b1). We aimed to define the molecular pathways of endogenous GC synthesis along the respiratory tree to provide a basis for understanding how local GC synthesis contributes to tissue homeostasis.MethodsExpression of steroidogenic enzymes in murine lung epithelium was analyzed by macroscopic and laser capture microdissection, followed by RT‐qPCR. Flow cytometry analysis was performed to identify the cellular source of steroidogenic enzymes. Additionally, the induction of steroidogenic enzyme expression in the lung was analyzed after lipopolysaccharide (LPS) injection. mRNA and protein expression of steroidogenic enzymes was confirmed in human lung tissue by RT‐qPCR and immunohistochemistry. Furthermore, GC synthesis was examined in ex vivo cultures of fresh tissue from mice and human lobectomy patients.ResultsWe observed that the murine and human lung tissue differentially expresses synthesis pathway‐determining enzymes along the respiratory tree. We detected Hsd11b1 expression in bronchial, alveolar, club and basal epithelial cells, whereas Cyp11b1 expression was detectable only in tracheal epithelial cells of mice. Accordingly, de novo synthesis of bioactive GC occurred in the large conducting airways, whereas reactivation occurred everywhere along the respiratory tree. Strikingly, Cyp11b1 but not Hsd11b1 expression was enhanced in the trachea upon LPS injection in mice.ConclusionWe report here the differential synthesis of bioactive GC along the murine and human respiratory tree. Thus, extra‐adrenal de novo GC synthesis and reactivation may differentially contribute to the regulation of immunological and inflammatory processes in the lung.

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Immune escape of colorectal tumours via local LRH‐1/Cyp11b1‐mediated synthesis of immunosuppressive glucocorticoids

Cited by 7 publications

References 53 publications

Local glucocorticoid synthesis regulates house dust mite-induced airway hypersensitivity in mice

Local glucocorticoid synthesis regulates house dust mite-induced airway hypersensitivity in mice

Mometasone Furoate Inhibits the Progression of Head and Neck Squamous Cell Carcinoma via Regulating Protein Tyrosine Phosphatase Non-Receptor Type 11

Glucocorticoids are differentially synthesized along the murine and human respiratory tree

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