Steroid receptor coactivator-3 differentially regulates the inflammatory response in peritoneal macrophages

Steroid receptor coactivator-3 (SRC-3) is a transcriptional coactivator that plays an important role in the regulation of cytokine mRNA translation. In the present study, SCR-3 gene knockout mice were used to study the effects of SCR-3 on the regulation of the inflammatory response in peritoneal macrophages induced by lipopolysaccharides (LPS). Peritoneal macrophages (PMs) of SRC-3(-/-) mice showed a decrease in the release of TNF-alpha, IL-1 beta and IL-6, and an increase in the release of IL-10. Furthermore, results of RT-PCR also showed that levels of TNF-alpha, IL-1 beta and IL-6 mRNA expression were significantly lower, while the level of IL-10 mRNA expression was higher in the SRC-3(-/-) mice, compared to those of wild-type mice, following treatment with LPS (p<0.01). In addition, western blotting revealed that: i) the extent of reduction of the glucocorticoid receptor in PMs from SRC-3(-/-) mice was significantly lower than that in wild-type mice (p<0.01); ii) the extent of increase of AP-1 in PMS from SRC-3(-/-) mice was significantly lower than that in wild-type mice (p<0.01); iii) the extent of increase of NF-kappa B p65 in PMs from SRC-3(-/-) mice was significantly higher than that in wild-type mice (p<0.01). Collectively, our studies revealed that SRC-3 may play a key role in the maintenance of innate immunity. Furthermore, absence of the SRC-3 protein may result in the partial loss of inflammation and phagocytosis barrier function, including suppression of LPS-induced transcriptional activity, release of TNF-alpha, IL-1 beta and IL-6, and obstruction of the function of phagocytes and elimination of bacteria, as well as their production.