In:
Cellular Physiology and Biochemistry, S. Karger AG, Vol. 38, No. 2 ( 2016), p. 801-808
Abstract:
Background/Aims: The counterbalance of macrophage migration inhibitory factor (MIF) and Gremlin-1 is a useful tool to predict the acuity of coronary artery disease (CAD) and plaque stability. Gremlin1 is an endogenous antagonist of MIF and therefore influences plaque vulnerability. This study was designed to elucidate the mechanistic basis determining the biophysical binding of Gremlin-1 to MIF. Methods: An in silico model suggested that several charged C-terminal amino acids are crucial in mediating Gremlin-1/MIF-binding. We produced several single amino acid exchange mutants of Gremlin-1 by site-directed mutagenesis. These Gremlin-1 mutants were tested for their ability to reduce MIF effects on monocytes. Results: We observed that the critical element of the Gremlin-1 molecule for regulating MIF-induced chemotactic activity lies at the C-terminal region. A single amino acid exchange of an arginine to an alanine residue is sufficient to abolish the antagonistic effect of Gremlin-1 on MIF. Therefore, the Gremlin-1 mutant R172A failed to reduce MIF-induced monocyte differentiation into macrophages. Conclusion: Gremlin-1 C-terminus is essential for antagonizing MIF effects. Our results could offer a novel strategy utilizing Gremlin-1 to target pro-inflammatory effects of MIF in various diseases.
Type of Medium:
Online Resource
ISSN:
1015-8987
,
1421-9778
Language:
English
Publisher:
S. Karger AG
Publication Date:
2016
detail.hit.zdb_id:
1482056-0
SSG:
12
SSG:
15,3
