A novel potential target of IL-35-regulated JAK/STAT signaling pathway in lupus nephritis.

Clin Transl Med

Department of Allergy, Immunology and Rheumatology, Guangzhou Women and Children's Medical Center, Guangzhou Meidcal University, Guangzhou, China.

Published: February 2021

Background: In this study, we have investigated the potential regulatory mechanisms of IL-35 to relieve lupus nephritis (LN) through regulating Janus kinase (JAK)/signal transducers and activators of transcription (STAT) signaling pathway in mesangial cells.

Results: Among 105 significant differentially expressed proteins (DEPs) between juvenile systemic lupus erythematosus (JSLE) patients with LN and healthy controls, LAIR1, PDGFRβ, VTN, EPHB4, and EPHA4 were downregulated in JSLE-LN. They consist of an interactive network with PTPN11 and FN1, which involved in IL-35-related JAK/STAT signaling pathway. Besides, urinary LAIR1 was significantly correlated with JSLE-LN clinical parameters such as SLEDAI-2K, %CD19+ B, and %CD3+ T cells. Through bioinformatics analysis of co-immunoprecipitation with mass spectrometry results, including GO, KEGG, and STRING, five genes interacted with Lair1 were upregulated by IL-35, but only Myh10 was downregulated. Therefore, we presumed an interactive network among these DEPs, JAK/STAT, and IL-35. Moreover, the downregulated phosphorylated (p)-STAT3, p-p38 MAPK, and p-ERK, and the upregulated p-JAK2/p-STAT1/4 in IL-35 overexpressed mesangial cells, and RNA-sequencing results validated the potential regulatory mechanisms of IL-35 in alleviating JSLE-LN disease. Moreover, the relieved histopathological features of nephritis including urine protein and leukocyte scores, a decreased %CD90 αSMA mesangial cells and pro-inflammatory cytokines, the inactivated JAK/STAT signals and the significant upregulated Tregs in spleen, thymus and peripheral blood were validated in Tregs and IL-35 overexpression plasmid-treated lupus mice.

Conclusions: Our study provided a reference proteomic map of urinary biomarkers for JSLE-LN and elucidated evidence that IL-35 may regulate the interactive network of LAIR1-PTPN11-JAK-STAT-FN1 to affect JAK/STAT and MAPK signaling pathways to alleviate inflammation in JSLE-LN. This finding may provide a further prospective mechanism for JSLE-LN clinical treatment.

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7851357PMC
http://dx.doi.org/10.1002/ctm2.309DOI Listing

Publication Analysis

Top Keywords

signaling pathway
12
interactive network
12
jak/stat signaling
8
lupus nephritis
8
potential regulatory
8
regulatory mechanisms
8
mechanisms il-35
8
jsle-ln clinical
8
mesangial cells
8
il-35
7

Similar Publications

Glycobiology of psoriasis: A review.

J Autoimmun

January 2025

Department of Immunology, School of Basic Medical Sciences, NHC Key Laboratory of Medical Immunology, Peking University, No.38, Xueyuan Road, Haidian, Beijing, 100191, China. Electronic address:

Psoriasis is a chronic inflammatory skin disease with etiologies related to genetics, immunity, and the environment. It is characterized by excessive proliferation of keratinocytes and infiltration of inflammatory immune cells. Glycosylation is a post-translational modification of proteins that plays important roles in cell adhesion, signal transduction, and immune cell activation.

View Article and Find Full Text PDF

Bruton's tyrosine kinase (BTK) is a major drug target in immune cells. The membrane-binding pleckstrin homology and tec homology (PH-TH) domains of BTK are required for signaling. Dimerization of the PH-TH module strongly stimulates the kinase activity of BTK in vitro.

View Article and Find Full Text PDF

Bone mineral density (BMD), an important marker of bone health, is regulated by a complex interaction of proteins. Plasma proteomic analyses can contribute to identification of proteins associated with changes in BMD. This may be especially informative in stages of bone accrual and peak BMD achievement (i.

View Article and Find Full Text PDF

Cadmium is a non-essential element and neurotoxin that causes neuroinflammation, which leads to neurodegenerative diseases and brain cancer. To date, there are no specific or effective therapeutic agents to control inflammation and alleviate cadmium-induced progressive destruction of brain cells. Fluoroquinolones (FQs), widely used antimicrobials with effective blood-brain barrier penetration, show promise in being repurposed as anti-inflammatory drugs.

View Article and Find Full Text PDF

Background: Fracture disrupts the integrity and continuity of the bone, leading to symptoms such as pain, tenderness, swelling, and bruising. Rhizoma Musae is a medicinal material frequently utilized in the Miao ethnic region of Guizhou Province, China. However, its specific mechanism of action in treating fractures remains unknown.

View Article and Find Full Text PDF

Want AI Summaries of new PubMed Abstracts delivered to your In-box?

Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!