FSL-1, a Toll-like Receptor 2/6 Agonist, Induces Expression of Interleukin-1α in the Presence of 27-hydroxycholesterol

Abstract

We investigated the question of whether cholesterol catabolite can influence expression of inflammatory cytokines via Toll-like receptors (TLR) in monocytic cells. Treatment of THP-1 monocytic cells with 27-hydroxycholesterol (27OHChol) resulted in induction of gene transcription of TLR6 and elevated level of cell surface TLR6. Addition of FSL-1, a TLR6 agonist, to 27OHChol-treated cells resulted in transcription of the IL-1α gene and enhanced secretion of the corresponding gene product. However, cholesterol did not affect TLR6 expression, and addition of FSL-1 to cholesterol-treated cells did not induce expression of IL-1α. Using pharmacological inhibitors, we investigated molecular mechanisms underlying the expression of TLR6 and IL-1α. Treatment with Akt inhibitor IV or U0126 resulted in significantly attenuated expression of TLR6 and IL-1α induced by 27OHChol and 27OHChol plus FSL-1, respectively. In addition, treatment with LY294002, SB202190, or SP600125 resulted in significantly attenuated secretion of IL-1α. These results indicate that 27OHChol can induce inflammation by augmentation of TLR6-mediated production of IL-1α in monocytic cells via multiple signaling pathways.

The entanglement of NASH and atherosclerosis

“…In vitro studies, however, have found that 27-HC can also have pro-inflammatory effects on macrophages and other tissues (121)(122)(123)(124)(125), which contradicts our findings in Chapter 5. One possible explanation for these observations is that 27-HC also functions as of a selective estrogen receptor modulator.…”

27-Oxygenated cholesterol induces expression of CXCL8 in macrophages via NF-κB and CD88

“…Polymerase chain reaction (PCR) and real-time PCR were performed using primers after reverse-transcription of total RNAs, as previously described [12]. The primers were mouse GAPDH: 5 0 -acacattgggggtaggaaca-3 0 (forward) and 5 0 -aactttggcattgtggaagg-3 0 (reverse); mouse IL-8: 5 0 -ttctttgcctgctgctcata-3 0 (forward) and 5 0 -caaggctgcagaatttgaga-3 0 (reverse); human GAPDH: 5 0 -gagtcaacggatttggtcct-3 0 (forward) and 5 0 -tgtggtcatgagtccttcca-3 0 (reverse); human IL-8: 5 0 -gtgcagttttgccaaggagt-3 0 (forward) and 5 0 -acttctccacaaccctctgc-3 0 (reverse); human CD88: 5 0 -gccttggtcatctttgcagt-3 0 (forward) and 5 0 -caggaaggagggtatggtca-3 0 (reverse).…”

SIG1459: A novel phytyl‐cysteine derived TLR2 modulator with in vitro and clinical anti‐acne activity

“…IL‐8 was previously shown to be induced by TLR2 and is one of the highest upregulated genes in acne lesions . IL‐1α was previously shown to be induced by C. acnes , but not TLR2/TLR6 ligand . Interestingly, SIG1459 was found to have selective, albeit potent anti‐inflammatory response to TLR2/2 homodimers and TLR2/TLR6 heterodimers, identified by their known activating ligands.…”