Estrogen decreases TNF gene expression by blocking JNK activity and the resulting production of c-Jun and JunD

Abstract

Central to the bone-sparing effect of estrogen (E 2 ) is its ability to block the monocytic production of the osteoclastogenic cytokine TNF-α (TNF). However, the mechanism by which E 2 downregulates TNF production is presently unknown. Transient transfection studies in HeLa cells, an E 2 receptor-negative line, suggest that E 2 inhibits TNF gene expression through an effect mediated by estrogen receptor β (ERβ). We also report that in RAW 264.7 cells, an E 2 receptor-positive murine monocytic line, E 2 downregulates cytokine-induced TNF gene expression by decreasing the activity of the Jun NH 2 -terminal kinase (JNK). The resulting diminished phosphorylation of c-Jun and JunD at their NH 2 -termini decreases the ability of these nuclear proteins to autostimulate the expression of the c-Jun and JunD genes, thus leading to lower production of c-Jun and JunD. The consequent decrease in the nuclear levels of c-Jun and JunD leads to diminished binding of c-Jun/c-Fos and JunD/c-Fos heterodimers to the AP-1 consensus sequence in the TNF promoter and, thus, to decreased transactivation of the TNF gene.

Multiple facets of junD gene expression are atypical among AP-1 family members

“…Downregulation of JNK by estrogen decreases JunD phosphorylation, which in turn decreases expression of the junD mRNA. These observations indicate that phosphorylation is necessary for JunD transcriptional transactivation of the junD promoter and that JNK stimulates the autoregulatory loop that modulates junD expression (Srivastava et al, 1999). Although the 43 Nterminal residues of JunD do not bind JNK (and do not promote ubiquitination, as discussed above), residues 49-59 of JunD provide a low-affinity docking domain for JNK that is necessary for phosphorylation (Figure 1, efficient phosphorylation is designated by the red squares labeled Pi) (Kallunki et al, 1996;Fuchs et al, 1997;Yazgan and Pfarr, 2002).…”

Impact of LIMK1, MMP2 and TNF-α variations for intracranial aneurysm in Japanese population

“…34 In addition, several reports showed that estrogen is known to inhibit TNF-a activity and reduced estrogen levels in post-menopausal women predispose to a higher incidence of aneurysm development. [35][36][37][38] Interestingly, there were reports showing that significant differences in the levels of TNF-a production when females and males stimulated under certain physiological condition, such as psychological stress and early alcohol-induced liver injury. 39,40 In our study, the risk allele of rs1799724 (À857T) are known to have a significantly higher level of TNF-a production from concanavalin Aactivated peripheral blood mononuclear cells, 41 implying the importance of this variant in IA development, particularly in female IA.…”

Estrogen is a modulator of vascular inflammation

“…Estrogen supplementation also reduces TNFa levels in cells of monocyte/macrophage lineage through involving the non-ERE transcription factor AP-1. Surprisingly, ERb rather than ERa plays the key role in this effect (20). In addition, estrogen acting through ERa modulates the postreceptor TNFa effects through NF-kB inhibition and consequently reduces adhesion molecule expression and leukocyte recruitment in endothelial cells (21).…”