Chloroquine attenuates TLR3/IFN-β signaling in cultured normal human mesangial cells: A possible protective effect against renal damage in lupus nephritis

• Published in: Modern rheumatology 2017-11, Vol.27 (6), p.1004-1009
• Main Authors: Imaizumi, Tadaatsu, Hayakari, Ryo, Matsumiya, Tomoh, Yoshida, Hidemi, Tsuruga, Kazushi, Watanabe, Shojiro, Kawaguchi, Shogo, Tanaka, Hiroshi
• Format: Article
• Language: English
• Subjects: Antirheumatic Agents - pharmacology; Cells, Cultured; Chloroquine; Chloroquine - pharmacology; Humans; Interferon-beta - genetics; Interferon-beta - metabolism; lupus nephritis; Lupus Nephritis - metabolism; mesangial cells; Mesangial Cells - drug effects; Mesangial Cells - metabolism; NF-kappa B - genetics; NF-kappa B - metabolism; NF-κB; Signal Transduction; STAT1 Transcription Factor - genetics; STAT1 Transcription Factor - metabolism; TLR3; Toll-Like Receptor 3 - genetics; Toll-Like Receptor 3 - metabolism
• ISSN: 1439-7595; 1439-7609
• DOI: 10.1080/14397595.2017.1289646

Background: Chloroquine has been reported to protect against renal damage in lupus nephritis (LN); however, its detailed mechanism in glomerular inflammation remains unclear. Upregulation of the type-I interferon (IFN) system plays a pivotal role in LN pathogenesis, therefore, we examined whether chloroquine inhibits toll-like receptor 3 (TLR3)/IFN-β signaling in cultured normal human mesangial cells (MCs). Methods: We examined chloroquine effect on the representative TLR3/IFN-β-signaling axis, TLR3/IFN-β/retinoic acid-inducible gene-I (RIG-I)/CCL5 in MCs treated with polyinosinic-polycytidylic acid (poly IC), a synthetic viral dsRNA analog and analyzed the expression of these molecules using reverse transcriptase-polymerase chain reaction and enzyme-linked immunosorbent assay (ELISA). Furthermore, we subjected MCs to RNA interference against NF-κB p65. Results: Pretreatment of cells with chloroquine attenuated IFN-β, RIG-I and CCL5 expression and phosphorylation of STAT1 induced by poly IC, but not IFN-β-induced phosphorylation of STAT1 and RIG-I expression induced by IFN-β. Knockdown of p65 inhibited the poly IC-induced IFN-β expression, and chloroquine pretreatment decreased the nuclear poly IC-induced translocation of NF-κB p65 in MCs. Conclusion: These results suggest that chloroquine attenuates mesangial TLR3 signaling in the early phase of NF-κB activation. Considering that TLRs/type-I IFNs signaling is implicated in LN pathogenesis, our results may further support regional renoprotective effects of chloroquine in treating LN.