Regulatory effect of IL-38 on NF-κB pathway in systemic lupus erythematosus

Jiyun Zhang; Nurshati Tabush; Chune Wei; Li Luo

doi:10.1016/j.imbio.2022.152322

Regulatory effect of IL-38 on NF-κB pathway in systemic lupus erythematosus

Immunobiology. 2023 Mar;228(2):152322. doi: 10.1016/j.imbio.2022.152322. Epub 2022 Dec 30.

Authors

Jiyun Zhang¹, Nurshati Tabush², Chune Wei², Li Luo³

Affiliations

¹ Department of Rheumatology and Immunology, The First Affiliated Hospital of Xinjiang Medical University, Urumqi 830058, Xinjiang, China; Department of Rheumatology and Immunology, The Second Affiliated Hospital of Xinjiang Medical University, Urumqi 830063, Xinjiang, China.
² Department of Rheumatology and Immunology, The Second Affiliated Hospital of Xinjiang Medical University, Urumqi 830063, Xinjiang, China.
³ Department of Rheumatology and Immunology, The First Affiliated Hospital of Xinjiang Medical University, Urumqi 830058, Xinjiang, China. Electronic address: Luol2022@sina.com.

PMID: 36621308
DOI: 10.1016/j.imbio.2022.152322

Abstract

Background: IL-38 is a newly identified cytokine that exhibits immunosuppression effects. However, there are few studies focusing on the effects and mechanisms of IL-38 in the systemic lupus erythematosus (SLE).

Aim: We investigated the effects and mechanisms of IL-38 on NF-κB signaling pathway in SLE.

Methods: Levels of IL-38, IL-36R, IL-1RAcP, IKKα/β, NF-κB, TNF-α and anti-dsDNA antibody levels in peripheral blood of SLE patients, and in peripheral blood and kidney tissues of MRL/lpr mice, were examined with real-time PCR, ELISA, Western blot and immunohistochemistry. Pathological changes of kidney were detected with PAS staining. Recombinant human IL-38 protein and IL-38 siRNA were used to intervene the PBMCs of SLE patients and MRL/lpr mice.

Results: The mRNA and protein levels of IL-38 in peripheral blood of SLE patients decreased and were positively correlated. The mRNA and protein levels of IKKα/β, NF-κB, and TNF-α increased, especially in patients with active SLE. There was a negative correlation between IL-38 and the levels of IKKα/β, NF-κB and TNF-α in SLE patients. In vitro experiments showed that the levels of IKKα/β, NF-κB and TNF-α, and anti-dsDNA antibodies decreased in PBMCs of SLE patients after treatment with human recombinant IL-38 protein. These effects were reversed after IL-38 siRNA intervention. Consistent results were obtained on IL-38, IKKα/β, NF-κB, and TNF-α in MRL/lpr lupus mice after treatment with IL-38 protein or IL-38 shRNA. Additionally, kidney function (reflected by creatinine and blood urea nitrogen), anti-dsDNA antibody, complement C3, and urinary protein levels decreased after treatment with IL-38 protein but increased after IL-38 shRNA treatment. PAS staining showed IL-38 protein treatment induced mild hyperplasia of glomerular mesangial cells and a small amount of lymphocyte infiltration. However, these were aggravated after IL-38 shRNA treatment.

Conclusion: IL-38 may be involved in the occurrence and development of SLE by regulating the NF-κB signaling pathway. This study only discussed the relationship between IL-38 and NF-κB, and more biological functions of IL-38 need to be further studied.

Keywords: Interleukin-1 receptor helper protein (IL-1RAcP); Interleukin-36 receptor (IL-36R); Interleukin-38 (IL-38); Nuclear factor-Kappa B (NF-κB); Systemic lupus erythematosus (SLE).

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Humans
I-kappa B Kinase
Interleukins
Lupus Erythematosus, Systemic*
Mice
Mice, Inbred MRL lpr
NF-kappa B* / metabolism
RNA, Messenger
RNA, Small Interfering
Tumor Necrosis Factor-alpha / metabolism

Substances

NF-kappa B
Tumor Necrosis Factor-alpha
I-kappa B Kinase
RNA, Small Interfering
RNA, Messenger
IL-38 protein, human
Interleukins