IL-15, a survival factor for kidney epithelial cells, counteracts apoptosis and inflammation during nephritis

Shinozaki, Michiya; Hirahashi, Junichi; Lebedeva, Tatiana; Liew, Foo Y.; Salant, David J.; Maron, Ruth; Kelley, Vicki Rubin

doi:10.1172/jci0214574

Cited by 73 publications

(63 citation statements)

References 53 publications

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“…The human epithelial cells of various tissues produce IL-15, which acts not only on immune cells (e.g., IELs in the gut), but also on epithelial cells, mainly via its anti-apoptotic action [17], [18], [19], [20]. Thus, it was shown that human and mouse renal tubular epithelial cells (RPTEC) constitutively express the receptor IL-15Rαβγ [15] and secrete the cytokine IL-15 [21], which plays an important role in renal physiology as an autocrine survival factor.…”

Section: Introductionmentioning

confidence: 99%

“…Thus, it was shown that human and mouse renal tubular epithelial cells (RPTEC) constitutively express the receptor IL-15Rαβγ [15] and secrete the cytokine IL-15 [21], which plays an important role in renal physiology as an autocrine survival factor. Indeed, increased sensitivity of cells to apoptosis is observed in the damaged kidney of IL-15−/−, IL-15Rα−/− knockout mice or during acute renal injury induced by different protocols that induce a decrease in IL-15 production by epithelial cells [20], [22]. IL-15 enhances intestinal barrier function by promoting the formation of tight junctions between epithelial cells [23].…”

Section: Introductionmentioning

confidence: 99%

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Interleukin-15 Plays a Central Role in Human Kidney Physiology and Cancer through the γc Signaling Pathway

et al. 2012

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The ability of Interleukin-15 (IL-15) to activate many immune antitumor mechanisms renders the cytokine a good candidate for the therapy of solid tumors, particularly renal cell carcinoma. Although IL-15 is being currently used in clinical trials, the function of the cytokine on kidney's components has not been extensively studied; we thus investigated the role of IL-15 on normal and tumor renal epithelial cells. Herein, we analyzed the expression and the biological functions of IL-15 in normal renal proximal tubuli (RPTEC) and in their neoplastic counterparts, the renal clear cell carcinomas (RCC). This study shows that RPTEC express a functional heterotrimeric IL-15Rαβγc complex whose stimulation with physiologic concentrations of rhIL-15 is sufficient to inhibit epithelial mesenchymal transition (EMT) commitment preserving E-cadherin expression. Indeed, IL-15 is not only a survival factor for epithelial cells, but it can also preserve the renal epithelial phenotype through the γc-signaling pathway, demonstrating that the cytokine possess a wide range of action in epithelial homeostasis. In contrast, in RCC in vitro and in vivo studies reveal a defect in the expression of γc-receptor and JAK3 associated kinase, which strongly impacts IL-15 signaling. Indeed, in the absence of the γc/JAK3 couple we demonstrate the assembly of an unprecedented functional high affinity IL-15Rαβ heterodimer, that in response to physiologic concentrations of IL-15, triggers an unbalanced signal causing the down-regulation of the tumor suppressor gene E-cadherin, favoring RCC EMT process. Remarkably, the rescue of IL-15/γc-dependent signaling (STAT5), by co-transfecting γc and JAK3 in RCC, inhibits EMT reversion. In conclusion, these data highlight the central role of IL-15 and γc-receptor signaling in renal homeostasis through the control of E-cadherin expression and preservation of epithelial phenotype both in RPTEC (up-regulation) and RCC (down-regulation).

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Interleukin-15 Plays a Central Role in Human Kidney Physiology and Cancer through the γc Signaling Pathway

et al. 2012

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“…24 Moreover, IL-15 signaling has been shown to function as a protective agent against cell death in several immune and non-immune cell types. 11, 14 These studies indicate that the protective capacity of IL-15 is underpinned by the ability of the IL-15 receptor complex to activate pro-survival pathways. 25 To this end, each receptor subunit within the IL-15R complex has a distinct binding and signaling capacity.…”

Section: Discussionmentioning

confidence: 99%

“…Additionally, it has been shown to protect against cell death in several non-immune cell types. 12, 14 IL-15 inhibits TNF-alpha mediated apoptosis within L929 murine fibroblasts, 15 and functions as a pro-survival autocrine factor in renal epithelial cells 14 and murine microglia. 12 To reduce apoptosis IL-15 signals though the IL-15 receptor system.…”

Section: Introductionmentioning

confidence: 99%

Il-15

Yeghiazarians

Honbo

Imhof

et al. 2014

Journal of Cardiovascular Pharmacology

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Cardiovascular disease is the leading cause of death in Western countries. A major limitation of current treatments is the inability to efficiently repair or replace dead myocardium. Recently, stem cell based therapies have been explored as an avenue to circumvent current therapeutic limitations. Overall, these therapies appear to result in small improvements in the contractile function of the heart. The exact mechanism(s) of action that underlie these improvements remain unknown and it is believed that paracrine effects play a significant role. Previously, we had reported that an extract derived from bone marrow cells (BMC), in the absence of any live cell, contained cardio-protective soluble factors. In this study, we identify IL-15 as a putative cardio-protectant within the BMC paracrine profile. Using an in vitro culture system, we assessed the ability of IL-15 to protect cardiomyocytes under hypoxic conditions. For the first time, we have identified IL-15 receptors on the surface of cardiomyocytes and delineated the signaling system by which hypoxic cardiomyocytes may be protected from cellular death and rescued from oxidative stress with IL-15 treatment.

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“…Recently, IL-15 was shown to induce differentiation of CD105 + renal CSCs isolated from human renal carcinomas (Azzi et al, 2011). Based on previous studies that had shown that IL-15 acted as a survival factor in renal tubular epithelial cells via autocrine-paracrine loops, the authors identified IL-15 as a potential candidate (Shinozaki et al, 2002). Other studies have shown that IL-15 upregulates E-cadherin expression through γc chain signaling pathway and blocks EMT in renal tubular epithelial cells ( Figure 2 ) (Giron-Michel et al, 2012, 2013).…”

Section: Interleukinsmentioning

confidence: 99%

Targeting Strategies for Renal Cell Carcinoma: From Renal Cancer Cells to Renal Cancer Stem Cells

Yuan

GuiXian

et al. 2016

Front. Pharmacol.

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Renal cell carcinoma (RCC) is a common form of urologic tumor that originates from the highly heterogeneous epithelium of renal tubules. Over the last decade, targeting therapies to renal cancer cells have transformed clinical care for RCC. Recently, it was proposed that renal cancer stem cells (CSCs) isolated from renal carcinomas were responsible for driving tumor growth and resistance to conventional chemotherapy and radiotherapy, according to the theory of CSCs; this has provided the rationale for therapies targeting this aggressive cell population. Precise identification of renal CSC populations and the complete cell hierarchy will accurately inform characterization of disease subtypes. This will ultimately contribute to more personalized and targeted therapies. Here, we summarize potential targeting strategies for renal cancer cells and renal CSCs, including tyrosine kinase inhibitors, mammalian target of rapamycin inhibitors (mTOR), interleukins, CSC marker inhibitors, bone morphogenetic protein-2, antibody drug conjugates, and nanomedicine. In conclusion, targeting therapies for RCC represent new directions for exploration and clinical investigation and they plant a seed of hope for advanced clinical care.

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IL-15, a survival factor for kidney epithelial cells, counteracts apoptosis and inflammation during nephritis

Cited by 73 publications

References 53 publications

Interleukin-15 Plays a Central Role in Human Kidney Physiology and Cancer through the γc Signaling Pathway

Interleukin-15 Plays a Central Role in Human Kidney Physiology and Cancer through the γc Signaling Pathway

Il-15

Targeting Strategies for Renal Cell Carcinoma: From Renal Cancer Cells to Renal Cancer Stem Cells

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