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.jpg): Failed to open stream: No such file or directory in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 117 J+Biol+Chem
2016 ; 291
(45
): 23628-23644
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Mineralocorticoid Receptor (MR) trans-Activation of Inflammatory AP-1 Signaling:
DEPENDENCE ON DNA SEQUENCE, MR CONFORMATION, AND AP-1 FAMILY MEMBER EXPRESSION
#MMPMID27650495
Dougherty EJ
; Elinoff JM
; Ferreyra GA
; Hou A
; Cai R
; Sun J
; Blaine KP
; Wang S
; Danner RL
J Biol Chem
2016[Nov]; 291
(45
): 23628-23644
PMID27650495
show ga
Glucocorticoids are commonly used to treat inflammatory disorders. The
glucocorticoid receptor (GR) can tether to inflammatory transcription factor
complexes, such as NF?B and AP-1, and trans-repress the transcription of
cytokines, chemokines, and adhesion molecules. In contrast, aldosterone and the
mineralocorticoid receptor (MR) primarily promote cardiovascular inflammation by
incompletely understood mechanisms. Although MR has been shown to weakly repress
NF?B, its role in modulating AP-1 has not been established. Here, the effects of
GR and MR on NF?B and AP-1 signaling were directly compared using a variety of
ligands, two different AP-1 consensus sequences, GR and MR DNA-binding domain
mutants, and siRNA knockdown or overexpression of core AP-1 family members. Both
GR and MR repressed an NF?B reporter without influencing p65 or p50 binding to
DNA. Likewise, neither GR nor MR affected AP-1 binding, but repression or
activation of AP-1 reporters occurred in a ligand-, AP-1 consensus sequence-, and
AP-1 family member-specific manner. Notably, aldosterone interactions with both
GR and MR demonstrated a potential to activate AP-1. DNA-binding domain mutations
that eliminated the ability of GR and MR to cis-activate a hormone response
element-driven reporter variably affected the strength and polarity of these
responses. Importantly, MR modulation of NF?B and AP-1 signaling was consistent
with a trans-mechanism, and AP-1 effects were confirmed for specific gene targets
in primary human cells. Steroid nuclear receptor trans-effects on inflammatory
signaling are context-dependent and influenced by nuclear receptor conformation,
DNA sequence, and the expression of heterologous binding partners. Aldosterone
activation of AP-1 may contribute to its proinflammatory effects in the
vasculature.