Activity of the growth hormone‐releasing hormone antagonist MIA602 and its underlying mechanisms of action in sarcoidosis‐like granuloma

Abstract

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, RNAseq analysis and flow cytometry. Results. MIA602 decreases the levels of IL-2, IL-2R, IL-7, IL-12, IL-17A and TNF-a 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.

Antagonist of Growth Hormone-Releasing Hormone Potentiates the Antitumor Effect of Pemetrexed and Cisplatin in Pleural Mesothelioma

“…Among these analogs, MIA-602 and MIA-690 showed potent suppressive effects on the growth of many cancers, including lung, gastric and colorectal cancers, where they exerted anti-inflammatory, antioxidative and proapoptotic functions [ 23 , 24 , 25 ]. Importantly, MIA-602, also reduced inflammation and fibrosis in a mouse model of lung injury, by inhibiting inflammatory pathways, such as signal transducer and activator of transcription 3 (STAT3) and nuclear factor kappa-B (NF-kB) [ 26 , 27 ], and decreased inflammation in sarcoidosis-like granuloma [ 28 ]. Furthermore, we recently demonstrated that MIA-602 and MIA-690, as single agents, inhibit the growth of human PM cell lines and primary cells in vitro, and exert strong antitumor effects in vivo in PM mice, by blunting proliferative and oncogenic pathways, as well as expression of tumor insulin-like growth factor 1 (IGF-1) and vascular endothelial growth factor (VEGF) [ 29 ].…”

Anti-inflammatory Properties of the Alpha-Melanocyte-Stimulating Hormone in Models of Granulomatous Inflammation

“…We collected their left lungs for pathology after removing blood. We used H&E staining to determine inflammatory pathology [ 11 ]. For IHC, we used primary antibodies (CD68, PD-1, PD-L1, CD30) and secondary antibodies, all purchased from Cell Signaling Technology, Beverly, MA, USA [ 11 ].…”

“…We used H&E staining to determine inflammatory pathology [ 11 ]. For IHC, we used primary antibodies (CD68, PD-1, PD-L1, CD30) and secondary antibodies, all purchased from Cell Signaling Technology, Beverly, MA, USA [ 11 ]. ABC Elite kit (Cat# PK-6200 Vector Laboratories, Inc. Burlingame, CA, USA) was used to detect immunoreaction.…”

“…We used the CD30 marker to measure lymphocyte activation [ 12 ], CD68 to quantify macrophages [ 13 ], and PD1 and PD-L1 markers to evaluate granuloma formation [ 14 ]. A pathologist evaluated three fields (100X power magnification) to score lung inflammation, as we reported before [ 11 ].…”

Interplay Between the Immune and Endocrine Systems in the Lung: Implications for TB Susceptibility

“…At mRNA level MIA-602 downregulates pathways involved in adaptive immune responses including T cell activation and differentiation, T cell signaling and cytokine production ( 54 ). In a sarcoidosis granuloma model, GHRHR inhibition results in reduced IL-12 and IL-17A production ( 54 , 55 ). Thus, MIA-602 demonstrates the contribution of GHRHR to adaptive immunity and T cell function, and that GHRHR is a potential candidate for managing these responses when they are excessive, such as in granulomatous diseases.…”