RT Journal Article
SR Electronic
T1 Activity of the GHRH Antagonist MIA602 and its Underlying Mechanisms of Action in sarcoidosis
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.08.19.257915
DO 10.1101/2020.08.19.257915
A1 Chongxu Zhang
A1 Runxia Tian
A1 Emilee M Dreifus
A1 Gregory Holt
A1 Renzhi Cai
A1 Anthony Griswold
A1 Pablo Bejarano
A1 Robert Jackson
A1 Andrew V. Schally
A1 Mehdi Mirsaeidi
YR 2020
UL http://biorxiv.org/content/early/2020/08/20/2020.08.19.257915.abstract
AB Growth hormone releasing hormone (GHRH) is a potent stimulator of 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 remains unknown. 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. MIA602 decreases levels of IL2, IL12, and IL17A in in vitro granuloma model.We show further that the anti-inflammatory effect of MIA602 appears to be mediated by reduction in CD45++CD68+ cells in granulomatous tissue and upregulation in PD-1 expression in macrophages.In analysis of expression of proteins involved in the mitochondrial stage of apoptosis, we show that MIA602 increases the levels of caspase 3, BCL-xL/BAK dimer, and MCl-1/Bak dimer in granuloma. These findings indicate that MIA602 may not induce apoptosis.The clinical relevance of our findings further suggest that HGRH-R is potentially a target for treatment of granulomatous disease and MIA602 possibly a novel therapeutic agent for sarcoidosis.Competing Interest StatementThe authors have declared no competing interest.