Abstract: FR-PO463
Inhibition of IL-18 Ameliorates Lipopolysaccharide-Induced Peritoneal Fibrosis in Mice
Session Information
- Peritoneal Dialysis: Current Topics
November 04, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
Abstract Time: 10:00 AM - 12:00 PM
Category: Dialysis
- 702 Dialysis: Home Dialysis and Peritoneal Dialysis
Authors
- Shichijo, Satoru, Ehime Daigaku Daigakuin Igakukei Kenkyuka Igakubu, Toon, Ehime, Japan
- Kukida, Masayoshi, Ehime Daigaku Daigakuin Igakukei Kenkyuka Igakubu, Toon, Ehime, Japan
- Miyake, Itsuki, Ehime Daigaku Daigakuin Igakukei Kenkyuka Igakubu, Toon, Ehime, Japan
- Makita, Ayu, Ehime Daigaku Daigakuin Igakukei Kenkyuka Igakubu, Toon, Ehime, Japan
- Aono, Jun, Ehime Daigaku Daigakuin Igakukei Kenkyuka Igakubu, Toon, Ehime, Japan
- Yamaguchi, Osamu, Ehime Daigaku Daigakuin Igakukei Kenkyuka Igakubu, Toon, Ehime, Japan
Background
Peritoneal dialysis (PD)-related bacterial peritonitis causes peritoneal fibrosis, leading to peritoneal deterioration and discontinuation of PD. Preventing peritoneal fibrosis is essential for the long-term PD, while there is no established treatment for peritoneal fibrosis. Interleukin (IL)-18 is a member of the IL-1 family of cytokines. We have previously demonstrated that IL-18 is involved in the pathophysiology of renal interstitial fibrosis. This study examined the role of IL-18 on the progression of peritonitis-induced peritoneal fibrosis.
Methods
We examined the effects of IL-18 deletion on peritoneal fibrosis using 8-week-old male C57BL/6J (WT) and IL-18-knockout (IL-18−/−) mice. Either vehicle or LPS (10mg/kg lipopolysaccharide, dissolved in 2ml saline) was injected to these mice once a week and sacrificed at days 15 after the first injection. Subsequently, mouse embryonic fibroblasts (MEF) from the E13.5 embryos of WT and IL-18−/− mice were extracted and incubated with 10ng/ml recombinant IL-18 to investigate the direct impacts of IL-18 on fibroblast in vitro . IL-18 binding protein (BP), a constitutively secreted protein, prevents IL-18 binding to its receptor. Since our results supported that IL-18 promoted fibroblast-mediated peritoneal fibrosis, we tested whether IL-18 BP is a therapeutic tool in LPS-induced peritoneal fibrosis. LPS-infused WT mice were also intraperitoneally administrated with either vehicle or 200μg/kg IL-18 BP.
Results
LPS induced significant peritoneal thickening with fibroblast proliferation compared with the vehicle injection in WT mice. The peritoneal fibrosis was attenuated in IL-18−/− mice. To examine these mechanisms, mice peritoneum were evaluated at days 2. LPS mainly induced macrophage infiltration in the peritoneum, which was attenuated by IL-18 deletion. Recombinant IL-18 increased the mRNA expression of TGF-β and CTGF in MEF from WT and IL-18−/− mice, equivalently. Both LPS- and IL-18 BP-injected mice showed less peritoneum thickening and fibroblast proliferation compared with only LPS-injected mice.
Conclusion
These data indicate IL-18 plays a pivotal role on LPS-induced peritoneal fibrosis. IL-18BP has a previously unrecognized therapeutic potential for peritonitis-induced fibrosis in PD patients.