IL-36α Regulates Tubulointerstitial Inflammation in the Mouse Kidney

Ichii, Osamu; Kimura, Junko; Okamura, Tadashi; Horino, Taro; Nakamura, Teppei; Sasaki, Hayato; Elewa, Yaser Hosny Ali; Kon, Yasuhiro

doi:10.3389/fimmu.2017.01346

Cited by 20 publications

(36 citation statements)

References 33 publications

(47 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Like other cytokines, IL‐36α is expressed primarily in immuno‐competent cells, but is induced in renal tubular cells in patients and rodent models with AKI and CKD [9,12]. In mice, unilateral ureteral obstruction (UUO), ischemia–reperfusion injury (IRI), glomerulonephritis, and diabetic nephropathy were reported to induce expression of IL‐36α in renal tubular cells [9,13,14]. In humans, urine levels of IL‐36α were reported to increase in patients with AKI [12] and CKD [9].…”

Section: Discussionmentioning

confidence: 99%

Interleukin‐36α as a potential biomarker for renal tubular damage induced by dietary phosphate load

et al. 2020

View full text Add to dashboard Cite

Excessive intake of phosphate has been known to induce renal tubular damage and interstitial inflammation, leading to acute kidney injury or chronic kidney disease in rodents and humans. However, sensitive and early biomarkers for phosphate‐induced kidney damage remain to be identified. Our previous RNA sequencing analysis of renal gene expression identified interleukin‐36α (IL‐36α) as a gene significantly upregulated by dietary phosphate load in mice. To determine the time course and dose dependency of renal IL‐36α expression induced by dietary phosphate load, we placed mice with or without uninephrectomy on a diet containing either 0.35%, 1.0%, 1.5%, or 2.0% inorganic phosphate for 10 days, 4 weeks, or 8 weeks and evaluated renal expression of IL‐36α and other markers of tubular damage and inflammation by quantitative RT‐PCR, immunoblot analysis, and immunohistochemistry. We found that IL‐36α expression was induced in distal convoluted tubules and correlated with phosphate excretion per nephron. The increase in IL‐36α expression was simultaneous with but more robust in amplitude than the increase in tubular damage markers such as Osteopontin and neutrophil gelatinase‐associated lipocalin, preceding the increase in expression of other inflammatory cytokines, including transforming growth factor‐α, interleukin‐1β, and transforming growth factor‐β1. We conclude that IL‐36α serves as a marker that reflects the degree of phosphate load excreted per nephron and of associated kidney damage.

show abstract

Section: Discussionmentioning

confidence: 99%

Interleukin‐36α as a potential biomarker for renal tubular damage induced by dietary phosphate load

et al. 2020

View full text Add to dashboard Cite

show abstract

“…In the beginning of this study, we first detected the mRNA levels of 10 proinflammatory ILs both in the renal tissues of Thy-1N rats (in vivo) and in the GMCs treated with sublytic C5b-9 (in vitro), and found that mRNA of IL-6, IL-23, and IL-36a was greatly increased. Given that our previous study on Thy-1N rats has revealed the mechanism of sublytic C5b-9-induced IL-6 synthesis (5) and other researchers have reported that IL-23 and IL-36a contribute to inflammatory diseases (17,22,45,46), we selected IL-23 and IL-36a to further explore the mechanism of IL-23 and IL-36a synthesis in the GMCs upon sublytic C5b-9 attack in Thy-1N rats.…”

Section: Discussionmentioning

confidence: 99%

Sublytic C5b-9 Induces IL-23 and IL-36a Production by Glomerular Mesangial Cells via PCAF-Mediated KLF4 Acetylation in Rat Thy-1 Nephritis

Zhang

Xie

et al. 2018

The Journal of Immunology

View full text Add to dashboard Cite

Sublytic C5b-9 formation on glomerular mesangial cells in rat Thy-1 nephritis (Thy-1N), a model of human mesangioproliferative glomerulonephritis, is accompanied by the production of proinflammatory cytokines, but the relationship between sublytic C5b-9 and cytokine synthesis and the underlying mechanism remains unclear. To explore the problems mentioned above, in this study, we first examined the levels of proinflammatory ILs (e.g., IL-23 and IL-36a) as well as transcription factor (KLF4) and coactivator (PCAF) in the renal tissues of Thy-1N rats and in the glomerular mesangial cell line (HBZY-1) stimulated by sublytic C5b-9. Then, we further determined the role of KLF4 and PCAF in sublytic C5b-9–induced IL-23 and IL-36a production as well as the related mechanism. Our results showed that the levels of KLF4, PCAF, IL-23, and IL-36a were obviously elevated. Mechanistic investigation revealed that sublytic C5b-9 stimulation could increase IL-23 and IL-36a synthesis through KLF4 and PCAF upregulation, and KLF4 and PCAF could form a complex, binding to the IL-23 or IL-36a promoter in a KLF4-dependent manner, causing gene transcription. Importantly, KLF4 acetylation by PCAF contributed to sublytic C5b-9–induced IL-23 and IL-36a transcription. Besides, the KLF4 binding regions on IL-23 or IL-36a promoters and the KLF4 lysine site acetylated by PCAF were identified. Furthermore, silencing renal KLF4 or PCAF gene could significantly inhibit IL-23 or IL-36a secretion and tissue damage of Thy-1N rats. Collectively, these findings implicate that the KLF4/PCAF interaction and KLF4 acetylation by PCAF play a pivotal role in the sublytic C5b-9–mediated IL-23 and IL-36a production of Thy-1N rats.

show abstract

“…2 ), 5 , 6 9 11 16 26 suggesting that the length of primary cilia reflects the status of diseases and that cilia length changes are influenced by various disease-associated factors, including inflammatory cytokines, ROS, HIFs, and regulators of the cellular cytoskeleton and cell cycle. 7 8 9 25 26 27 42 Ichii et al 24 recently reported that interleukin (IL)-1 receptor-like 2 (IL-1RL2), an IL-36α receptor protein, was expressed at the primary cilia of distal tubular epithelial cells in the contralateral kidney after unilateral ureteral obstruction (UUO), which induced the elongation of primary cilia. 8 11 24 They proposed that the elongation of primary cilia may increase the sensitivity of cells to urine flow and IL-36α.…”

Section: Implication Of Primary Cilia Length In Kidney Diseasesmentioning

confidence: 99%

“… 2 21 22 In the kidney, the primary cilium length is dynamically altered under the influence of not only physiological factors including renal flow and the cell cycle, but also pathological factors including reactive oxygen species (ROS), oxidative stress, and cytokines. 7 8 9 23 24 25 26 Recently we and others found that acute kidney injury (AKI) and chronic kidney disease (CKD) change primary cilium lengths in the kidney epithelial cells. 5 6 7 8 9 11 27 Although it is unclear whether the change in primary cilia length is caused by these diseases because of the lack of evidence using animals with regulated cilia length, accumulated data indicate that the length of the primary cilium is associated with the progression of diseases.…”

Section: Introductionmentioning

confidence: 99%

Can Tissue Cilia Lengths and Urine Cilia Proteins Be Markers of Kidney Diseases?

Park

2018

Chonnam Med J

View full text Add to dashboard Cite

The primary cilium is an organelle which consists of a microtubule in the core and a surrounding cilia membrane, and has long been recognized as a “vestigial organelle”. However, new evidence demonstrates that the primary cilium has a notable effect on signal transduction in the cell and is associated with some genetic and non-genetic diseases. In the kidney, the primary cilium protrudes into the Bowman's space and the tubular lumen from the apical side of epithelial cells. The length of primary cilia is dynamically altered during the normal cell cycle, being shortened by retraction into the cell body at the entry of cell division and elongated at differentiation. Furthermore, the length of primary cilia is also dynamically changed in the cells, as a result and/or cause, during the progression of various kidney diseases including acute kidney injury and chronic kidney disease. Notably, recent data has demonstrated that the shortening of the primary cilium in the cell is associated with fragmentation, apart from retraction into the cell body, in the progression of diseases and that the fragmented primary cilia are released into the urine. This data reveals that the alteration of primary cilia length could be related to the progression of diseases. This review will consider if primary cilia length alteration is associated with the progression of kidney diseases and if the length of tissue primary cilia and the presence or increase of cilia proteins in the urine is indicative of kidney diseases.

show abstract

IL-36α Regulates Tubulointerstitial Inflammation in the Mouse Kidney

Cited by 20 publications

References 33 publications

Interleukin‐36α as a potential biomarker for renal tubular damage induced by dietary phosphate load

Interleukin‐36α as a potential biomarker for renal tubular damage induced by dietary phosphate load

Sublytic C5b-9 Induces IL-23 and IL-36a Production by Glomerular Mesangial Cells via PCAF-Mediated KLF4 Acetylation in Rat Thy-1 Nephritis

Can Tissue Cilia Lengths and Urine Cilia Proteins Be Markers of Kidney Diseases?

Contact Info

Product

Resources

About