Physiological and molecular effects of interleukin-18 administration on the mouse kidney

Abstract

BackgroundThe cytokine interleukin-18 was originally identified as an interferon-γ-inducing proinflammatory factor; however, there is increasing evidence to suggest that it has non-immunological effects on physiological functions. We previously investigated the potential pathophysiological relationship between interleukin-18 and dyslipidemia, non-alcoholic fatty liver disease, and non-alcoholic steatohepatitis, and suggested interleukin-18 as a possible novel treatment for not only these diseases but also for cancer immunotherapy. Before clinical application, the effects of interleukin-18 on the kidney need to be determined. In the current study, we examined the kidney of interleukin-18 knockout (Il18−/−) mice and the effects of interleukin-18 on the kidney following intravenous administration of recombinant interleukin-18.MethodsIl18−/− male mice were generated on the C57Bl/6 background and littermate C57Bl/6 Il18+/+ male mice were used as controls. To assess kidney damage, serum creatinine and blood urea nitrogen levels were measured and histopathological analysis was performed. For molecular analysis, microarray and quantitative reverse transcription PCR was performed using mice 6 and 12 weeks old. To evaluate the short- and long-term effects of interleukin-18 on the kidney, recombinant interleukin-18 was administered for 2 and 12 weeks, respectively.ResultsCompared with Il18+/+ mice, Il18−/− mice developed kidney failure in their youth-6 weeks of age, but the condition was observed to improve as the mice aged, even though dyslipidemia, arteriosclerosis, and higher insulin resistance occurred. Analyses of potential molecular mechanisms involved in the onset of early kidney failure in Il18−/− mice identified a number of associated genes, such as Itgam, Nov, and Ppard. Intravenous administration of recombinant interleukin-18 over both the short and long term showed no effects on the kidney despite significant improvement in metabolic diseases.ConclusionsShort- and long-term administration of interleukin-18 appeared to have no adverse effects on the kidney in these mice, suggesting that administration may be a safe and novel treatment for metabolic diseases and cancer.Electronic supplementary materialThe online version of this article (10.1186/s12967-018-1426-6) contains supplementary material, which is available to authorized users.

Deficiency in interleukin-18 promotes differentiation of brown adipose tissue resulting in fat accumulation despite dyslipidemia

“…Moreover, this study only focused on BAT. However, we are currently investigating the basic relationship between IL-18 and physiological homeostasis in other organs [ 10 , 11 ]. Furthermore, additional analysis is required, for example, analysis of the metabolic function of IL-18 in BAT under cold exposure should be performed.…”

“…The protocols for sample collection, mRNA purification, microarray, Ingenuity ® Pathway Analysis (IPA; Ingenuity ® Systems, Redwood, CA, USA) and quantitative reverse transcription PCR (qRT-PCR) have been described previously [ 10 , 11 , 28 ]. Mice were euthanized by decapitation at 10 a.m, and BATs were removed and immediately placed in liquid nitrogen, and then kept at − 80 °C until use.…”

“…Previous studies have reported that IL-18-deficient mice developed hyperphagia, obesity and insulin resistance [ 9 ]. Moreover, these mice presented with dyslipidemia, non-alcoholic fatty liver diseases (NAFLD) and non-alcoholic steatohepatitis (NASH), and they were also related to kidney function [ 10 , 11 ]. In human studies, the serum concentration of IL-18 was significantly higher in patients with type 2 diabetes mellitus and with metabolic syndrome than in healthy controls [ 12 , 13 ].…”

Analysis of genes linked to depressive‑like behaviors in interleukin‑18‑deficient mice: Gene expression profiles in the brain

“…An inactive 24-kDa precursor form of IL-18 is cleaved by activated caspase-1 to a mature 18-kDa active form (4)(5)(6)(7). In addition to its role as an inflammatory cytokine, IL-18 also serves a role in energy metabolism, and in the central nervous system it is involved in psychiatric disorders such as depression (8)(9)(10)(11)(12). Regarding energy homeostasis, IL-18 deficiency induces bulimia, corpulency and insulin resistance which resembles type 2 diabetes mellitus (8).…”

“…In the present study, candidate genes which may be involved in the induction of depressive-like behavioral changes were identified by comparing gene expression in the brains of Il18 +/+ and Il18 -/mice. At 12 weeks of age, a time at which Il18 -/mice start to exhibit depression-like behavioral changes, the genes with a |>1.5|-fold change were identified and analyzed using Ingenuity ® Pathway Analysis (IPA) as described previously (10,11). Subsequently, to explore candidate genes associated with depression at 12 weeks of age, microarray analysis was performed to compare expression at 6 and 12 weeks of age to screen for effector genes that induce depression.…”