25-Hydroxycholesterol

25-hydroxycholesterol is a side-chain oxysterol produced by cholesterol metabolism and secreted by macrophages in response to Toll-like receptor (TLR) activation. 25-hydroxycholesterol effectively and selectively inhibits IgA production by B cells, with an EC₅₀ of approximately 65nM^[1]. 25-hydroxycholesterol directly regulates lipid metabolism and inflammatory response in hepatocytes through LXR/SREBP-1 and IκBα/NFκB signaling^[2]. 25-hydroxycholesterol has antiviral effects and can also regulate transcriptional responses through AP-1 and act as an inflammatory amplifier ^[3].

In vitro, 25-hydroxycholesterol (5μM) stimulated mouse macrophages for 18 hours, and RNA expression was analyzed by microarray and seven members of the AP-1 family (Fos, Fosb, Fosl1, Fosl2, Jun, Junb, and Jund) was significantly up-regulated^[3]. Treatment of splenic B220⁺ cells with 25-hydroxycholesterol (250 nM) for 6 days resulted in CSR inhibition, thereby inhibiting IgA secretion, but addition on days 4 and 5 had no effect because of the occurrence of Ig heavy chain site rearrangement^[4]. 25-hydroxycholesterol (10⁻⁴, 10⁻⁵ and 10⁻⁶M) dose-dependently inhibits the growth of sparse smooth muscle cells in ethanol vehicles ^[5].

In vivo, 25-hydroxycholesterol (50 mg/kg; i.p.) upregulates Chop in the lungs of Ch25h^–/– mice, as well as the endoplasmic reticulum stress markers BiP and Atf4 ^[6]. 25-hydroxycholesterol (1.5mg/kg; i.v.) can protect rhesus monkeys from ZIKV virus infection, and 25-hydroxycholesterol (50mg/kg; i.p.) can also prevent ZIKV infection in mice and prevent microcephaly symptoms ^[7] .

References:

[1] McDonald JG, et al. Editorial: 25-Hydroxycholesterol: a new life in immunology[J]. J Leukoc Biol. 2010 Dec;88(6):1071-1072.

[2] Xu L , Bai Q , Rodriguez-Agudo D ,et al. Regulation of Hepatocyte Lipid Metabolism and Inflammatory Response by 25-Hydroxycholesterol and 25-Hydroxycholesterol-3-sulfate[J]. Lipids, 2010, 45(9): 821–832.

[3]Elizabeth S. Gold, Alan H. Diercks, Irina Podolsky, et al. 25-Hydroxycholesterol acts as an amplifier of inflammatory signaling[J]. PNAS, 2014,111 (29):10666-10671.

[4] Bauman D R , Bitmansour A D , Mcdonald J G ,et al.25-Hydroxycholesterol secreted by macrophages in response to Toll-like receptor activation suppresses immunoglobulin A production[J].Proceedings of the National Academy of Sciences, 2009, 106(39):16764-16769.

[5]Cox D C , Comi K , Goldstein A L .Effects of cholesterol and 25-hydroxycholesterol on smooth muscle cell and endothelial cell growth[J].Lipids, 1988, 23(2):85-88.

[6]Madenspacher JH, Morrell ED, McDonald JG, et al. 25-Hydroxycholesterol exacerbates vascular leak during acute lung injury[J]. JCI Insight. 2023  10;8(7):e155448.

[7]Li C , Deng Y Q , Wang S ,et al.25-Hydroxycholesterol Protects Host against Zika Virus Infection and Its Associated Microcephaly in a Mouse Model.[J].Immunity, 2017, 46(3):446.