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. 2024 Feb;83(Suppl 1):132-139.
doi: 10.1007/s00393-023-01319-4. Epub 2023 Feb 2.

MicroRNA-125b mediates Interferon-γ-induced downregulation of the vitamin D receptor in systemic lupus erythematosus

Yihong Gu  1 , Juan Tang  1 , Hao Zhang  1 , Qiongying Wu  1 , Linjuan Luo  1 , Jian Sun  2
Affiliations

MicroRNA-125b mediates Interferon-γ-induced downregulation of the vitamin D receptor in systemic lupus erythematosus

Yihong Gu et al. Z Rheumatol. 2024 Feb.

Abstract
in English, German

Background: The inflammatory factor interferon (IFN)-γ is related to the occurrence and development of systemic lupus erythematosus (SLE). The vitamin D receptor (VDR) has an anti-inflammatory effect and its downregulation is involved in the onset of SLE. Our previous studies have confirmed that the expression of VDR in SLE peripheral blood mononuclear cells (PBMCs) is downregulated, which is negatively correlated with disease activity and inflammation. However, the mechanism underlying VDR downregulation in SLE is unknown.

Methods: Based on the results of computer simulation analysis, the expression of VDR and four microRNAs (miR-17-3p, miR-34a, miR-346, and miR-125b) in SLE PBMC cells was analyzed under proinflammatory cytokine IFN‑γ treatment, and miR-125b was identified as the target miRNA. The relationship between IFN‑γ, miR-125b, and VDR was further assessed in THP‑1 cells.

Results: We showed that IFN‑γ inhibited the expression of VDR and miR-125b. Further study revealed that VDR mRNA was positively correlated with miR-125b in THP‑1 cells after IFN‑γ intervention. After transfection of miR-125b mimic or inhibitor, the expression of VDR in the miR-125b inhibitor group was lower than in the control group and miR-125b mimic group, while expression in the control group was lower than in miR-125b mimic group. Transfection of miR-125b inhibitor into THP‑1 cells could further promote the ability of IFN‑γ to inhibit VDR.

Conclusion: The decrease in VDR expression promotes development of inflammation and SLE. These data suggest that miR-125b may mediate inflammatory factor IFN-γ-induced downregulation of VDR in the pathogenesis of SLE.

Zusammenfassung: HINTERGRUND: Der Entzündungsfaktor Interferon‑γ (IFN-γ) steht mit dem Auftreten und der Entwicklung des systemischen Lupus erythematodes (SLE) in Zusammenhang. Der Vitamin-D-Rezeptor (VDR) weist einen antiinflammatorischen Effekt auf, seine Downregulation spielt beim Auftreten des SLE eine Rolle. Vorangegangene Studien der Autoren haben bestätigt, dass die Expression des VDR in mononukleären Zellen des periphereren Bluts (PBMC) bei SLE herabreguliert ist, was negativ mit der Krankheitsaktivität und Entzündungsprozessen korreliert ist. Allerdings ist der Mechanismus, der dieser VDR-Downregulation bei SLE zugrunde liegt, bisher unbekannt.

Methoden: Auf der Grundlage der Ergebnisse einer Computersimulationsanalyse wurde die Expression des VDR und von 4 MicroRNA (miR-17-3p, miR-34a, miR-346 und miR-125b) in SLE-PBMC-Zellen unter Behandlung mit dem proinflammatorischen Zytokin IFN‑γ analysiert, und miR-125b wurde als die Ziel-miRNA identifiziert. In THP-1-Zellen wurde der Zusammenhang zwischen IFN‑γ, miR-125b und VDR weiter untersucht.

Ergebnisse: Es wurde gezeigt, dass IFN‑γ die Expression des VDR und von miR-125b hemmt. Die weitere Untersuchung ergab, dass VDR-mRNA positiv mit miR-125b in THP-1-Zellen nach IFN-γ-Intervention korreliert war. Nach Transfektion mit einem Imitator von miR-125b („miR-125b mimic“) oder mit einem miR-125b-Inhibitor war die Expression des VDR in der miR-125b-Inhibitor-Gruppe niedriger als in der Kontrollgruppe und in der mit „miR-125b mimic“ behandelten Gruppe, während die Expression in der Kontrollgruppe niedriger als in der mit „miR-125b mimic“ behandelten Gruppe war. Die Transfektion des miR-125b-Inhibitors in THP-1-Zellen könnte die Fähigkeit von IFN‑γ, den VDR zu hemmen, weiter fördern.

Schlussfolgerung: Die Abnahme der VDR-Expression fördert die Entstehung von Entzündungsprozessen und SLE. Die vorliegenden Daten sprechen dafür, dass miR-125b möglicherweise die durch den inflammatorischen Faktor IFN‑γ induzierte Downregulation des VDR in der Pathogenese des SLE vermittelt.

Keywords: Inflammation; Interferon‑γ; MicroRNA-125b; Systemic lupus erythematosus; Vitamin D receptor.

PubMed Disclaimer

Conflict of interest statement

Y. Gu, J. Tang, H. Zhang, Q. Wu, L. Luo, and J. Sun declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
PBMCs were isolated from 24 subjects randomly selected from the SLE patients ex vivo in triplicate. Cultured PBMCs were treated with or without IFN‑γ (100 ng/ml) for 24 h before total RNA or cell lysates were harvested. VDR mRNA levels were quantified by real-time PCR in these two groups (n = 24 for each group). VDR protein levels were determined by western blotting in these subjects. Data are represented as mean ± SD; **p < 0.01 vs. corresponding without IFN‑γ group (Ctrl) value
Fig. 2
Fig. 2
PBMCs were isolated from 12 subjects randomly selected from the SLE patients ex vivo in triplicate. Cultured PBMCs were treated with or without IFN‑γ (100 ng/ml) for 24 h before total RNA or cell lysates were harvested. The miR-125b, miR-34a, miR-346, and miR-17-3p levels were measured by real-time PCR in these two groups (n = 12 for each group). Data are represented as mean ± SD; **p < 0.01 vs. corresponding without IFN‑γ group (Ctrl) value
Fig. 3
Fig. 3
Cultured THP‑1 cells were treated with 100 ng/ml IFN‑γ for different times as indicated before total RNA or cell lysates were harvested. VDR mRNA and miR-125b levels were (Fig. 3a) quantified by real-time PCR in these four groups (n = 3 for each group). Data are represented as mean ± SD. Further correlation analysis (Fig. 3b) between the two changes was analyzed by Pearson. Data were represented as mean ± SD; **p < 0.05
Fig. 4
Fig. 4
Cultured THP-1 cells with or without VDR overexpression (VDR-OE) were transfected with miR-125b mimic or inhibitor for 24 h before total RNA or cell lysates were harvested. VDR mRNA levels (Fig. 4a) were quantified by real-time PCR in these six groups (n = 3 for each group). VDR protein levels (Fig. 4b, c) were determined by western blotting in these subjects. Data were represented as mean ± SD; (**p < 0.01)
Fig. 5
Fig. 5
Cultured THP-1 cells with or without VDR overexpression (VDR-OE) were transfected with miR-125b inhibitor for 24 h and then treated with or without IFN‑γ (100 ng/ml) for 24 h before total RNA or cell lysates were harvested. VDR protein levels were determined by western blotting in these subjects. Data were represented as mean ± SD; ##p < 0.05 vs. corresponding without IFN-γ-treatment (NT) value, **p < 0.01
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