Activity of the growth hormone‐releasing hormone antagonist MIA602 and its underlying mechanisms of action in sarcoidosis‐like granuloma
| Autor: | Renzhi Cai, Abdolrazagh Hashemi Shahraki, Gregory E. Holt, Runxia Tian, Anthony J. Griswold, Robert M. Jackson, Pablo A. Bejarano, Chongxu Zhang, Emilee M Dreifus, Mehdi Mirsaeidi, Andrew V. Schally |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Pituitary gland
medicine.medical_specialty Immunology Immune system Downregulation and upregulation In vivo Internal medicine medicine Immunology and Allergy sarcoidosis granuloma GHRH antagonist General Nursing MIA602 Chemistry Antagonist Original Articles RC581-607 medicine.disease Growth hormone–releasing hormone medicine.anatomical_structure Endocrinology Granuloma Original Article Immunologic diseases. Allergy Hormone |
| Zdroj: | Clinical & Translational Immunology Clinical & Translational Immunology, Vol 10, Iss 7, Pp n/a-n/a (2021) |
| ISSN: | 2050-0068 |
| Popis: | Objectives Growth hormone‐releasing hormone (GHRH) is a potent stimulator of growth hormone (GH) secretion from the pituitary gland. Although GHRH is essential for the growth of immune cells, the regulatory effects of its antagonist in granulomatous disease remain unknown. Methods Here, we report expression of GHRH receptor (R) in human tissue with sarcoidosis granuloma and demonstrate the anti‐inflammatory effects of MIA602 (a GHRH antagonist) in two in vitro human granuloma models and an in vivo granuloma model using different methods including ELISA, immunohistochemistry, RNA‐seq analysis and flow cytometry. Results MIA602 decreases the levels of IL‐2, IL‐2R, IL‐7, IL‐12, IL‐17A and TNF‐α in an in vitro granuloma model. Further, we show that the anti‐inflammatory effect of MIA602 appears to be mediated by a reduction in CD45+CD68+ cells in granulomatous tissue and upregulation in PD‐1 expression in macrophages. Analysis of the expression of proteins involved in the mitochondrial stage of apoptosis showed that MIA602 increases the levels of caspase‐3, BCL‐xL/BAK dimer and MCl‐1/Bak dimer in the granuloma. These findings indicate that MIA602 may not induce apoptosis. Conclusions Our findings further suggest that GHRH‐R is potentially a clinical target for the treatment of granulomatous disease and that MIA602 may be used as a novel therapeutic agent for sarcoidosis. GHRH‐R is potentially a target for treatment of granulomatous diseases such as sarcoidosis, which could be blocked by growth hormone‐releasing hormone‐R antagonists such as MIA602 as novel therapeutic agents for sarcoidosis. |
| Databáze: | OpenAIRE |
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