Ninomiya Yuichi, Yasuda Toshimichi, Kawamoto Masashi, Yuge Osafumi, Okazaki Yasushi
Department of Immunology, Graduate School of Biomedical Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan.
J Steroid Biochem Mol Biol. 2007 Jan;103(1):44-50. doi: 10.1016/j.jsbmb.2006.07.009. Epub 2006 Oct 17.
Microsomal prostaglandin E synthase (mPGES)-1, which is dramatically induced in macrophages by inflammatory stimuli such as lipopolysaccharide (LPS), catalyzes the conversion of cyclooxygenase-2 (COX-2) reaction product prostaglandin H(2) (PGH(2)) into prostaglandin E(2) (PGE(2)). The mPGES-1-derived PGE(2) is thought to help regulate inflammatory responses. On the other hand, excess PGE(2) derived from mPGES-1 contributes to the development of inflammatory diseases such as arthritis and inflammatory pain. Here, we examined the effects of liver X receptor (LXR) ligands on LPS-induced mPGES-1 expression in murine peritoneal macrophages. The LXR ligands 22(R)-hydroxycholesterol (22R-HC) and T0901317 reduced LPS-induced expression of mPGES-1 mRNA and mPGES-1 protein as well as that of COX-2 protein. However, LXR ligands did not influence the expression of microsomal PGES-2 (mPGES-2) or cytosolic PGES (cPGES) protein. Consequently, LXR ligands suppressed the production of PGE(2) in macrophages. These results suggest that LXR ligands diminish PGE(2) production by inhibiting the LPS-induced gene expression of the COX-2-mPGES-1 axis in LPS-activated macrophages.
微粒体前列腺素E合酶（mPGES）-1在巨噬细胞中可被脂多糖（LPS）等炎症刺激显著诱导，它催化环氧合酶-2（COX-2）反应产物前列腺素H2（PGH2）转化为前列腺素E2（PGE2）。mPGES-1衍生的PGE2被认为有助于调节炎症反应。另一方面，mPGES-1衍生的过量PGE2会导致诸如关节炎和炎性疼痛等炎症性疾病的发展。在此，我们研究了肝脏X受体（LXR）配体对LPS诱导的小鼠腹腔巨噬细胞中mPGES-1表达的影响。LXR配体22（R）-羟基胆固醇（22R-HC）和T0901317降低了LPS诱导的mPGES-1 mRNA和mPGES-1蛋白的表达以及COX-2蛋白的表达。然而，LXR配体并未影响微粒体PGES-2（mPGES-2）或胞质PGES（cPGES）蛋白的表达。因此，LXR配体抑制了巨噬细胞中PGE2的产生。这些结果表明，LXR配体通过抑制LPS激活的巨噬细胞中COX-2-mPGES-1轴的LPS诱导基因表达来减少PGE2的产生。
