Working from within: how secretory leukocyte protease inhibitor regulates the expression of pro-inflammatory genes

Biochemistry and Cell Biology ◽

10.1139/bcb-2021-0284 ◽

2021 ◽

Author(s):

Tinsley C. Douglas ◽

Sari S Hannila

Keyword(s):

Gene Expression ◽

Protease Inhibitor ◽

Neutrophil Infiltration ◽

Serine Protease Inhibitor ◽

Secretory Leukocyte Protease Inhibitor ◽

Inflammatory Factor ◽

Murine Models ◽

Anti Inflammatory ◽

Additional Role ◽

Pro Inflammatory Cytokines

Secretory leukocyte protease inhibitor (SLPI) is a small but powerful member of the serine protease inhibitor family, which includes proteins such as elafin and alpha1 anti-trypsin. These proteins all have similar structure and antiprotease abilities, but SLPI has been found to have an additional role as an anti-inflammatory factor. It can inhibit the production of pro-inflammatory cytokines in cells stimulated with lipopolysaccharide, prevent neutrophil infiltration in murine models of lung and liver injury, and regulate the activity of the transcription factor NF-κB. In this review, we will revisit SLPI’s unique biochemistry, and then explore how its anti-inflammatory functions can be linked to more recent findings showing that SLPI can localize to the nuclei of cells, bind DNA, and act as a regulator of gene expression.

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SLPI is a critical mediator that controls PTH-induced bone formation

Nature Communications ◽

10.1038/s41467-021-22402-x ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Akito Morimoto ◽

Junichi Kikuta ◽

Keizo Nishikawa ◽

Takao Sudo ◽

Maki Uenaka ◽

...

Keyword(s):

Parathyroid Hormone ◽

Bone Resorption ◽

Bone Formation ◽

Protease Inhibitor ◽

Bone Metabolism ◽

Serine Protease ◽

Serine Protease Inhibitor ◽

Secretory Leukocyte Protease Inhibitor ◽

Bone Imaging ◽

Genetic Ablation

AbstractOsteoclastic bone resorption and osteoblastic bone formation/replenishment are closely coupled in bone metabolism. Anabolic parathyroid hormone (PTH), which is commonly used for treating osteoporosis, shifts the balance from osteoclastic to osteoblastic, although it is unclear how these cells are coordinately regulated by PTH. Here, we identify a serine protease inhibitor, secretory leukocyte protease inhibitor (SLPI), as a critical mediator that is involved in the PTH-mediated shift to the osteoblastic phase. Slpi is highly upregulated in osteoblasts by PTH, while genetic ablation of Slpi severely impairs PTH-induced bone formation. Slpi induction in osteoblasts enhances its differentiation, and increases osteoblast–osteoclast contact, thereby suppressing osteoclastic function. Intravital bone imaging reveals that the PTH-mediated association between osteoblasts and osteoclasts is disrupted in the absence of SLPI. Collectively, these results demonstrate that SLPI regulates the communication between osteoblasts and osteoclasts to promote PTH-induced bone anabolism.

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Comprehensive Comparison of Amnion Stromal Cells and Chorion Stromal Cells by RNA-Seq

International Journal of Molecular Sciences ◽

10.3390/ijms22041901 ◽

2021 ◽

Vol 22 (4) ◽

pp. 1901

Author(s):

Brielle Jones ◽

Chaoyang Li ◽

Min Sung Park ◽

Anne Lerch ◽

Vimal Jacob ◽

...

Keyword(s):

Gene Expression ◽

Stromal Cells ◽

Expression Profiles ◽

Expression Patterns ◽

Principal Component ◽

Differentially Expressed ◽

Inflammatory Factor ◽

Next Generation Sequencing Technology ◽

Angiogenic Potential ◽

Anti Inflammatory

Mesenchymal stromal cells derived from the fetal placenta, composed of an amnion membrane, chorion membrane, and umbilical cord, have emerged as promising sources for regenerative medicine. Here, we used next-generation sequencing technology to comprehensively compare amniotic stromal cells (ASCs) with chorionic stromal cells (CSCs) at the molecular and signaling levels. Principal component analysis showed a clear dichotomy of gene expression profiles between ASCs and CSCs. Unsupervised hierarchical clustering confirmed that the biological repeats of ASCs and CSCs were able to respectively group together. Supervised analysis identified differentially expressed genes, such as LMO3, HOXA11, and HOXA13, and differentially expressed isoforms, such as CXCL6 and HGF. Gene Ontology (GO) analysis showed that the GO terms of the extracellular matrix, angiogenesis, and cell adhesion were significantly enriched in CSCs. We further explored the factors associated with inflammation and angiogenesis using a multiplex assay. In comparison with ASCs, CSCs secreted higher levels of angiogenic factors, including angiogenin, VEGFA, HGF, and bFGF. The results of a tube formation assay proved that CSCs exhibited a strong angiogenic function. However, ASCs secreted two-fold more of an anti-inflammatory factor, TSG-6, than CSCs. In conclusion, our study demonstrated the differential gene expression patterns between ASCs and CSCs. CSCs have superior angiogenic potential, whereas ASCs exhibit increased anti-inflammatory properties.

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Expression of inter-alpha-trypsin inhibitor heavy chains in endometrium of cyclic and pregnant gilts

Reproduction ◽

10.1530/rep.0.1260621 ◽

2003 ◽

pp. 621-627 ◽

Cited By ~ 15

Author(s):

RD Geisert ◽

MD Ashworth ◽

Keyword(s):

Gene Expression ◽

Extracellular Matrix ◽

Western Blot ◽

Protease Inhibitor ◽

Early Pregnancy ◽

Trypsin Inhibitor ◽

Serine Protease Inhibitor ◽

Oestrous Cycle ◽

Heavy Chains ◽

Formation Of Complexes

Attachment of the placenta to the uterus in pigs involves extracellular interaction between the expanding trophoblastic membrane and the thick glycocalyx present on the uterine epithelial microvilli. Formation of complexes between members of inter-alpha-trypsin inhibitor family may function in the maintenance of the extracellular matrix. This study investigated the change in the inter-alpha-trypsin inhibitor heavy chains (ITIH1, ITIH2, ITIH3 and ITIH4) during the oestrous cycle and early pregnancy in pigs. Gene expression of ITIH1, ITIH2, ITIH3 and ITIH4 was detected in the endometrium of cyclic and pregnant gilts; however, gene expression of ITIH was not altered throughout the oestrous cycle or early pregnancy. Western blot analysis with an ITIH antiserum identified the possible linkage forms of ITIH with the serine protease inhibitor, bikunin. Pregnancy altered the release of the various inter-alpha-inhibitor forms from the endometrium during the period of trophoblastic attachment. The results from this study indicate that the inter-alpha-trypsin inhibitor family plays an important role in maintenance of the uterine surface glycocalyx during placental attachment in pigs.

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Wheat Germ Supplementation Increases Lactobacillaceae and Promotes an Anti-inflammatory Gut Milieu in C57BL/6 Mice Fed a High-Fat, High-Sucrose Diet

Journal of Nutrition ◽

10.1093/jn/nxz061 ◽

2019 ◽

Vol 149 (7) ◽

pp. 1107-1115 ◽

Cited By ~ 7

Author(s):

Babajide A Ojo ◽

Crystal O'Hara ◽

Lei Wu ◽

Guadalupe Davila El-Rassi ◽

Jerry W Ritchey ◽

...

Keyword(s):

Gene Expression ◽

Inflammatory Markers ◽

Wheat Germ ◽

Bacterial Population ◽

High Fat ◽

Sucrose Diet ◽

Small Intestinal ◽

Anti Inflammatory ◽

High Sucrose ◽

Pro Inflammatory Cytokines

ABSTRACT Background A link between high-fat diet consumption and obesity-related diseases is the disruption of the gut bacterial population, which promotes local and systemic inflammation. Wheat germ (WG) is rich in bioactive components with antioxidant and anti-inflammatory properties. Objective The aim of this study was to investigate the effects of WG supplementation in modulating the gut bacterial population and local and systemic inflammatory markers of mice fed a high-fat, high-sucrose (HFS) diet. Methods Six-week-old male C57BL/6 mice were randomly assigned to 4 groups (n = 12/group) and fed a control (C; 10% kcal fat, 10% kcal sucrose) or HFS (60% kcal fat, 20% kcal sucrose) diet with or without 10% WG (wt:wt) for 12 wk. Cecal bacteria was assessed via 16S rDNA sequencing, fecal short-chain fatty acids by GC, small intestinal CD4+ lymphocytes using flow cytometry, and gut antimicrobial peptide genes and inflammatory markers by quantitative polymerase chain reaction. Statistical analyses included Kruskal–Wallis/Dunn's test and 2-factor ANOVA using HFS and WG as factors. Results There was a 4-fold increase (P = 0.007) in the beneficial bacterial family, Lactobacillaceae, in the HFS + WG compared with the HFS group. Fecal propionic and n-butyric acids were elevated at least 2-fold in C + WG compared with the other groups (P < 0.0001). WG tended to increase (≥7%; P-trend = 0.12) small intestinal regulatory T cell:Th17 ratio, indicating a potential to induce an anti-inflammatory gut environment. WG elevated (≥35%) ileal gene expression of the anti-inflammatory cytokine Il10 compared to the unsupplemented groups (P = 0.038). Ileal gene expression of the antimicrobial peptides Reg3b and Reg3g was upregulated (≥95%) in the HFS + WG compared with other groups (P ≤ 0.040). WG reduced serum concentrations of the pro-inflammatory cytokines, interleukin (IL)-1B, IL-6, interferon-γ, and tumor necrosis factor-α (≥17%; P ≤ 0.012). Conclusions WG selectively increased gut Lactobacillaceae, upregulated ileal antimicrobial peptides, and attenuated circulating pro-inflammatory cytokines of C57BL/6 mice fed a HFS diet. These changes may be vital in preventing HFS diet-induced comorbidities.

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