Abstract
Although 17β-estradiol (E2) anti-inflammatory activity has been well described, very little is known about the effects of this hormone on the resolution phase of the inflammatory process. Here, we identified a previously unreported ERα-mediated effect of E2 on the inflammatory machinery. The study showed that the activation of the intracellular estrogen receptor shortens the LPS-induced pro-inflammatory phase and, by influencing the intrinsic and extrinsic programs, triggers the resolution of inflammation in RAW 264.7 cells. Through the regulation of the SOCS3 and STAT3 signaling pathways, E2 facilitates the progression of the inflammatory process toward the IL10-dependent “acquired deactivation” phenotype, which is responsible for tissue remodeling and the restoration of homeostatic conditions. The present study may provide an explanation for increased susceptibility to chronic inflammatory diseases in women after menopause, and it suggests novel anti-inflammatory treatments for such disorders.
Highlights
17β-estradiol (E2) anti-inflammatory activity has been well described, very little is known about the effects of this hormone on the resolution phase of the inflammatory process
The hypothesis that estrogens may play a role in protection against chronic inflammatory diseases stems from a large body of clinical and preclinical evidence that has demonstrated that a) the etiology and course of chronic inflammatory diseases is influenced by the menstrual cycle and pregnancy[1,2,3]; b) a significant increase in the incidence of disorders characterized by a strong inflammatory component is a hallmark of the cessation of ovarian functions[4]; and c) fertile female mammals are less prone than males to these diseases[5,6]
AS 1517499 prevention of ERα up-regulation by interleukin 4 (IL4) indicated the requirement of Signal Transducer and Activator of Transcription 6 (STAT6) to increase the ERα gene expression (Supplementary Fig. S2c). These results provided a potential explanation for the opposite effects of E2 on IL4-induced Arg[1] expression: in the presence of a functional STAT6 pathway, ERα content was significantly increased by IL4, leading E2 to act predominantly through ERα, which limited the expression of the M2 marker
Summary
17β-estradiol (E2) anti-inflammatory activity has been well described, very little is known about the effects of this hormone on the resolution phase of the inflammatory process. This is achieved with significant changes in the transcriptome and proteome: inflammatory stimuli (derived from microbes, damaged tissues or activated lymphocytes) induce macrophages to acquire the pro-inflammatory polarization or M1 consisting of the rapid activation of NF-κ B and the synthesis and secretion of pro-inflammatory cytokines (e.g., TNFα , IL1β , IL6, IL12, and IL23) and chemokines ( monocyte chemotactic protein-1, MCP1) These inflammatory compounds are responsible for the increased expression of cytotoxic mediators such as inducible nitric oxide synthase (iNOS). The antagonism by ICI 182,780 demonstrated the involvement of ERα or ERβ in the E2 interference of IL4-driven expression of the AA polarization marker (Fig. 1b) These results were confirmed using another macrophage cell line, J774A.1 (as shown in Supplementary Fig. S1b–e), suggesting that these findings were not restricted to RAW264.7. These results led us to conclude that the E2 interference of IL4 activity had to be ascribed to the liganded ERα
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