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. 2023 Oct 27;26(6):579.
doi: 10.3892/etm.2023.12278. eCollection 2023 Dec.

Hyperforin modulates MAPK/CCL11 signaling to reduce the inflammatory response of nasal mucosal epithelial cells caused by allergic rhinitis by targeting BCL6

Chen Xu  1 , Wen Su  1
Affiliations

Hyperforin modulates MAPK/CCL11 signaling to reduce the inflammatory response of nasal mucosal epithelial cells caused by allergic rhinitis by targeting BCL6

Chen Xu et al. Exp Ther Med. .

Abstract

Hyperforin is a type of bicyclic tetraketone with four isoprenoid chains extracted from Hypericum perforatum L. that has multiple biological activities such as anti-diabetes, antitumor and anti-inflammation. However, the role and potential mechanism of hyperforin in allergic rhinitis (AR) remains to be clarified. In the present study, cell viability was analyzed using Cell Counting Kit-8 assay, while inflammation was detected using ELISA and reverse transcription-quantitative PCR. Epithelial cell barrier damage was measured using western blotting and immunofluorescence staining. The expression levels of B-cell lymphoma 6 (BCL6) and the p38 MAPK/C-C motif chemokine 11 (CCL11) pathway were detected using western blotting. In addition, the association between hyperforin and BCL6 was analyzed by SWISS TargetPrediction, DisGeNET, Gene Ontology and Pathway databases. Molecular docking was performed using AutoDockTools 1.5.6 and Discovery Studio 4.5 software. The data demonstrated that there were 16 interlinking target genes of hyperforin with AR, in which BCL6 was the most relevant one with hyperforin in AR. The binding between hyperforin and BCL6 was verified, and molecular docking was modeled. The results revealed that hyperforin inhibited IL-13-induced nasal epithelial inflammatory cytokine release and repressed the damage to the cellular barrier from IL-13 stimulation. In addition, hyperforin activated BCL6 expression and significantly suppressed the expression of p38 MAPK/CCL11. Silencing of BCL6 reversed the effects of hyperforin on IL-13-induced inflammation and barrier damage. In summary, the present results revealed that hyperforin suppressed IL-13-induced nasal epithelial cell inflammation and barrier damage by targeting BCL6/p38 MAPK/CCL11, which may provide promising therapeutic targets for AR.

Keywords: B-cell lymphoma 6; C-C motif chemokine 11; allergic rhinitis; hyperforin; p38 MAPK.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Figure 1
Figure 1
Analysis of intersection genes between hyperforin and AR. (A) Intersection genes of hyperforin and AR were obtained using Venn diagrams. (B) Network of 16 intersection genes of hyperforin and AR was presented using the String database. Analysis of 16 intersection genes by the (C) GO and (D) Pathway databases. AR, allergic rhinitis; GO, Gene Ontology.
Figure 2
Figure 2
Hyperforin suppresses the release of nasal epithelial inflammatory cytokines induced by IL-13. (A) JME/CF15 cell viability was assessed using Cell Counting Kit-8 assay. The protein levels of (B) TNFα, (C) IL-1β and (D) IL-6 were evaluated using ELISA. The mRNA levels of (E) TNFα, (F) IL-1β and (G) IL-6 were evaluated using reverse transcription-quantitative PCR. *P<0.05, **P<0.01, ***P<0.001.
Figure 3
Figure 3
Hyperforin restrains IL-13-induced JME/CF15 cell barrier damage. (A) Protein levels of ZO-1, occludin and claudin 1 in JME/CF15 cells were measured using western blotting. (B) Immunofluorescence staining was used to detect the level of ZO-1 in IL-13-induced cells with or without hyperforin (magnification, x200). **P<0.01, ***P<0.001. ZO-1, zonula occludens-1.
Figure 4
Figure 4
Hyperforin increases BCL6 and inhibits the p38 MAPK/CCL11 pathway in IL-13-induced JME/CF15 cells. Molecular docking (A) 3D and (B) 2D diagram of the binding of hyperforin and BCL6. Western blotting was performed to detect the protein level of (C) BCL6 and (D) p-p38. (E) Protein level of CCL11 was evaluated using ELISA. *P<0.05, **P<0.01, ***P<0.001. BCL6, B-cell lymphoma 6; p-, phosphorylated; CCL11, C-C motif chemokine 11.
Figure 5
Figure 5
Hyperforin inhibits IL-13-induced nasal epithelial inflammation by activating BCL6. (A) mRNA level of BCL6 was evaluated by RT-qPCR. The protein levels of (B) TNFα, (C) IL-1β and (D) IL-6 were evaluated by ELISA. The mRNA levels of (E) TNFα, (F) IL-1β and (G) IL-6 were evaluated using RT-qPCR. **P<0.01, ***P<0.001. RT-qPCR, reverse transcription-quantitative PCR; BCL6, B-cell lymphoma 6; NC, negative control; siRNA, small interfering RNA.
Figure 6
Figure 6
Hyperforin suppresses IL-13-induced nasal epithelial cell barrier damage by activating BCL6. (A) Protein levels of ZO-1, occludin and claudin 1 in JME/CF15 cells were measured by western blotting. (B) Immunofluorescence staining was used to detect the level of ZO-1 in IL-13-induced cells with hyperforin in the presence and absence of siRNA-BCL6. **P<0.01, ***P<0.001. BCL6, B-cell lymphoma 6; ZO-1, zonula occludens-1; NC, negative control; siRNA, small interfering RNA.
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Grants and funding

Funding: The present study was supported by the Wuhan Medical Research Project (grant nos. WZ21Q05 and WZ20M01).