Chrysin Inhibits NF-κB-Dependent CCL5 Transcription by Targeting IκB Kinase in the Atopic Dermatitis-Like Inflammatory Microenvironment

Abstract

Chrysin (5,7-dihydroxyflavone) is a natural polyphenolic compound that induces an anti-inflammatory response. In this study, we investigated the molecular mechanism underlying the chrysin-induced suppression of C-C motif chemokine ligand 5 (CCL5) gene expression in atopic dermatitis (AD)-like inflammatory microenvironment. We showed that chrysin inhibited CCL5 expression at the transcriptional level through the suppression of nuclear factor kappa B (NF-κB) in the inflammatory environment. Chrysin could bind to the ATP-binding pocket of the inhibitor of κB (IκB) kinase (IKK) and, subsequently, prevent IκB degradation and NF-κB activation. The clinical efficacy of chrysin in targeting IKK was evaluated in 2,4-dinitrochlorobenzene-induced skin lesions in BALB/c mice. Our results suggested that chrysin prevented CCL5 expression by targeting IKK to reduce the infiltration of mast cells to the inflammatory sites and at least partially attenuate the inflammatory responses. These findings suggested that chrysin might be useful as a platform for the design and synthesis of small-molecule IKK-targeting drugs for the treatment of chronic inflammatory diseases, such as AD.

Chrysin Inhibits TNFα-Induced TSLP Expression through Downregulation of EGR1 Expression in Keratinocytes

“…Previous studies have shown that chrysin alleviates AD-like skin lesions in a mouse model [ 37 ] and reverses the NF-κB-mediated inhibition of C-C motif chemokine ligand (CCL) 5 [ 39 ]. TSLP plays a key role in AD progression, and TSLP upregulation is considered a hallmark of AD pathogenesis [ 31 , 32 ].…”

“…Chrysin has a pharmacological property that helps alleviate the clinical symptoms of AD by inhibiting the secretion of pro-inflammatory cytokines and chemokines [ 37 , 38 , 39 ]. TNFα is a major pro-inflammatory cytokine that is released from various immune cells and stromal cells.…”

“…NF-κB mediates TNFα-induced TSLP expression in human airway smooth muscle cells [ 43 ] and IL-1β-induced TSLP expression in intestinal epithelial cells [ 44 ]. We have previously reported that chrysin inhibits NF-κB activity by targeting the inhibitor of κB kinase, a protein encoded upstream of NF-κB and is involved in the proteolysis of the NF-κB inhibitor IκB [ 39 ]. Choi et al [ 37 ] also reported that chrysin inhibits TNFα/IFNγ-induced degradation of IκB, leading to the inhibition of nuclear translocation of NF-κB in HaCaT keratinocytes.…”

“…Immunostaining of the skin sections from the ear and neck was performed as previously described [ 39 ]. Briefly, after deparaffinization with xylene (three times for 10 min) and hydration with a graded ethanol series, the tissue sections were placed in 1 mM EDTA (pH 8.0) at 70 °C for 20 min.…”

“…It exhibits multiple pharmacological and therapeutic properties, including neuroprotective, anti-inflammatory, and anticancer properties [ 35 , 36 ]. Notably, chrysin is known to alleviate AD by inhibiting the production of multiple pro-inflammatory cytokines and chemokines [ 37 , 38 , 39 ]. Choi et al [ 37 ] have demonstrated that chrysin significantly inhibits the production of cytokines, Th2 chemokines, CCL17, and CCL22 by the downregulation of p38 MAPK, NF-κB, and STAT1 in TNFα/IFNγ-stimulated HaCaT keratinocytes.…”