Raloxifene and Two New Selective Estrogen Receptor Modulators (SERMs) Inducing M2-Macrophage Shift and High IL-10 and IL-1Ra Production
A new study published in the journal Inflammation indicates that in myeloid cells raloxifene and two new selective estrogen receptor modulators (SERMs) are able to induce a shift to M2-macrophage anti-inflammatory phenotype, characterized by high production of interleukin (IL)-10 and IL-1 receptor antagonist (IL-1Ra).
Estrogens exert pleiotropic immuno-modulatory and immuno-regulatory effects, contributing to the sexual dimorphism in immune responses, while abnormal estrogen levels and signaling also contribute to chronic inflammatory and autoimmune diseases. The immuno-regulatory effects of estrogens can be either pro- or anti-inflammatory depending on the types of organs and cells involved, but they, in general and overall, are anti-inflammatory.
Estrogens mediate anti-inflammatory effects mainly via the up-regulation of T helper (Th)2 lymphocytes and their cytokines, and by suppressing Th1 and possibly Th17 cellular responses. This anti-inflammatory shift also includes skewing the activity of macrophages towards the M2 phenotype, and altering the activity and the numbers of T regulatory cells (Treg).
Interestingly, a similar Th2-shift in immune responses is documented in the third trimester of pregnancy, a period characterized by exceptionally high estrogen levels. In pregnancy, placenta itself secretes IL-10, whereas estradiol and cortisol up-regulate lymphocyte IL-10, and along progesterone they potentiate Th2 lymphocytes and Th2-related cytokine production, mediating a Th2 shift towards humoral immunity.
The SERMs are mostly used in the prevention and treatment of breast cancer and postmenopausal osteoporosis. SERMs are competitive partial agonists of the estrogen receptors (ER) but act differently in diverse tissues. Thus, SERMs have the ability to act selectively as agonists or antagonists depending on the target tissue. Two SERMs are currently used in ER-positive breast cancer treatment: tamoxifen (Nolvadex) and raloxifen (Evista).
Table 1. Agonist or antagonist activities of ER ligands in estrogen-target tissues. From: What is a SERM and how does it work? Public domain, by Sylvain Lecomte, Thu Ha Pham and Farzad Pakdel; Inserm, University of Rennes, Rennes, France
In the study published in Inflammation, Lauri Polari and colleagues from the Institute of Biomedicine, University of Turku, Turku, Finland provided evidence that raloxifene and the two new SERM-type compounds, SERM2and SERM7 promoted M2 macrophage phenotype, alleviated NFκB activity and inhibited T cell proliferation.
More specifically the authors report that:
- raloxifene and the new SERM-type compounds increased the number of CD14+ CD163+ CD206+ suggesting that the IFN-γ polarized macrophages adopt a more anti-inflammatory phenotype.
- SERM2 and raloxifene increased the expression and secretion of the anti-inflammatory mediators IL-10 and IL-1Ra – the anti-inflammatory mediators and markers of M2-subtype macrophages.
- SERM-induced macrophages suppressed T cell proliferation following antigen activation in primary PBMCs.
- SERM2, SERM7, and raloxifene suppressed the TNFα-induced NFκB activation of the reporter monocytes.
In this study, SERM2 had the most significant stimulatory effect on M2 markers, and the authors speculate that this compound might suppress autoimmune reactions but still not disrupting the innate immunity against pathogens.
Of note, in the study, the ERα concentrations and ERα gene expression was the highest in both resting and IFN-γ/LPS-activated monocytes, over 100-fold higher to ERβ. Thus, the authors propose that ERα signaling plays a major role in M2-macrophage polarization.
As per the authors the new SERM compounds may hold therapeutic potential in chronic inflammation or autoimmune diseases. This study, as well as further research in this area may also provide new insights into the benefits or disadvantages of ER-modulating drugs currently used for, e.g., estrogen-sensitive cancers.
Source: Inflammation, 2018 Mar 24. doi: 10.1007/s10753-018-0763-1. [Epub ahead of print]
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