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Inhibition of ANXA2 regulated by SRF attenuates the development of severe acute pancreatitis by inhibiting the NF-κB signaling pathway

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Abstract

Background

Acute pancreatitis (AP) is an inflammatory process of the pancreas resulting from biliary obstruction or alcohol consumption. Approximately, 10–20% of AP can evolve into severe AP (SAP). In this study, we sought to explore the physiological roles of the transcription factor serum response factor (SRF), annexin A2 (ANXA2), and nuclear factor-kappaB (NF-κB) in SAP.

Methods

C57BL/6 mice and rat pancreatic acinar cells (AR42J) were used to establish an AP model in vivo and in vitro by cerulein with or without lipopolysaccharide (LPS). Production of pro-inflammatory cytokines (IL-1β and TNF-α) were examined by ELISA and immunoblotting analysis. Hematoxylin and eosin (HE) staining and TUNEL staining were performed to evaluate pathological changes in the course of AP. Apoptosis was examined by flow cytometric and immunoblotting analysis. Molecular interactions were tested by dual luciferase reporter, ChIP, and Co-IP assays.

Results

ANXA2 was overexpressed in AP and correlated to the severity of AP. ANXA2 knockdown rescued pancreatic acinar cells against inflammation and apoptosis induced by cerulein with or without LPS. Mechanistic investigations revealed that SRF bound with the ANXA2 promoter region and repressed its expression. ANXA2 could activate the NF-κB signaling pathway by inducing the nuclear translocation of p50. SRF-mediated transcriptional repression of ANXA2-protected pancreatic acinar cells against AP-like injury through repressing the NF-κB signaling pathway.

Conclusion

Our study highlighted a regulatory network consisting of SRF, ANXA2, and NF-κB that was involved in AP progression, possibly providing some novel targets for treating SAP.

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Abbreviations

AP:

Acute pancreatitis

MAP:

Mild acute pancreatitis

SAP:

Severe acute pancreatitis

LPS:

Lipopolysaccharide

ATCC:

American type culture collection

FBS:

Fetal bovine serum

QNZ:

Quinazoline

ELISA:

Enzyme-linked immunosorbent assay

IL-1β:

Interleukin-1β

TNF-ɑ:

Tumor necrosis factor-ɑ

HE staining:

Hematoxylin and eosin staining

TUNEL staining:

TdT-mediated dUTP-biotin nick end-labeling staining

ChIP:

Chromatin immunoprecipitation

FITC:

Fluorescein isothiocyanate

PBS:

Phosphate-buffered saline

DAPI:

4′,6-Diamidino-2-phenylindole

cDNA:

Complementary DNA

qRT-PCR:

Quantitative real-time polymerase chain reaction

SDS-PAGE:

Sodium dodecyl sulfate–polyacrylamide gel electrophoresis

ANOVA:

One-way analysis of variance

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Acknowledgements

We would like to give our sincere gratitude to the reviewers for their constructive comments.

All protocols for mouse used and euthanasia followed were approved by the Institutional Animal Care and Use Committee of The Third Xiangya Hospital of Central South University.

Funding

This work was supported by Natural Science Foundation of Hunan Province (No. 2019JJ40472) and Natural Science Foundation of Hunan Province (grant no: 2021JJ40955).

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Authors and Affiliations

  1. The Department of Gerontology, The Third Xiangya Hospital of Central South University, No. 138, Tongzipo Road, Yuelu District, Changsha, 410013, Hunan Province, People’s Republic of China

    Guanxiu Tang

  2. The Department of Intensive Care Unit (ICU), The Third Xiangya Hospital of Central South University, No. 138, Tongzipo Road, Yuelu District, Changsha, 410013, Hunan Province, People’s Republic of China

    Can Yu, Min Gao, Zuoliang Liu, Bingchang Yang, Mingshi Yang & Shangping Zhao

  3. The Department of Gastrointestinal Surgery, The Third Xiangya Hospital of Central South University, No. 138, Tongzipo Road, Yuelu District, Changsha, 410013, Hunan Province, People’s Republic of China

    Kaimin Xiang

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  1. Guanxiu Tang
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Correspondence to Shangping Zhao.

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Tang, G., Yu, C., Xiang, K. et al. Inhibition of ANXA2 regulated by SRF attenuates the development of severe acute pancreatitis by inhibiting the NF-κB signaling pathway. Inflamm. Res. 71, 1067–1078 (2022). https://doi.org/10.1007/s00011-022-01609-8

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  • DOI: https://doi.org/10.1007/s00011-022-01609-8

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