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Alpha in cisplatin nephrotoxicity Correspondence:Z dong, department of cellular biology and anatomy, medical college of georgia, 1459 laney walker boulevard, augusta, georgia 30912, usa.Using chimeric models, reeves and colleagues now demonstrate that resident kidney cells, rather than infiltrating immune cells, are the major producers of tnf.Blockade of tnf attenuates inflammation and associated kidney injury. Cisplatin, a widely used chemotherapeutic agent, is used to treat a variety of cancers.A major drawback of this drug is its side effects in normal cells and tissues, prominently toxicity in the kidneys.Over 30% of patients develop renal problems during cisplatin treatment, which limits the use and efficacy of cisplatin in cancer therapy.The cellular and molecular mechanism of cisplatin nephrotoxicity is a topic of intense investigation, is very complex, and involves multiple factors and processes, including a robust inflammatory response and, ultimately, death of renal tubular cells.1 Tumor necrosis factor(Tnf)Is a key player in the inflammatory response during cisplatin nephrotoxicity.Tnf production was induced under the pathological condition.2, 3 and 4 Importantly, in TNFdeficient mice, the production and secretion of proinflammatory cytokines and chemokines were attenuated, and this was associated with amelioration of acute kidney injury and renal failure during cisplatin treatment.Similar observations were shown for tnf inhibition by pharmacological inhibitors and neutralizing antibodies.3 Together, these studies have demonstrated a critical role for TNF in mounting the inflammatory response during cisplatin nephrotoxicity and the ensuing kidney tissue damage and acute renal failure. Given the role of tnf in cisplatin nephrotoxicity, several important questions remain.How does cisplatin induce tnf expression?Where is tnf produced and by what cells?How does tnf stimulate the proinflammatory response?By what mechanism does tnf induce kidney injury and renal failure?Reeves and colleagues5(This issue)Have now provided significant insights into these important questions.Specifically, they have demonstrated that resident cells of the kidneys, rather than infiltrating inflammatory cells, are the major contributors of tnf production during cisplatin nephrotoxicity.5 When considering cytokine and chemokine production under pathological conditions, many of us tend to think about an origin from cells of the immune system.However, in the kidney, there are a variety of cells that can efficiently produce and secrete cytokines and chemokines.For example, production of tnf has been shown in mesangial cells, glomerular cells, endothelial cells, and renal tubular cells.So, is tnf produced by infiltrating immune cells or parenchymal cells of the kidneys?To address this question, reeves and colleagues5 created chimeric models in which bone marrow of recipient animals was ablated and then reconstituted with bone marrow derived from wildtype(Wt)Or tnf knocKout(Ko)Donor mice.The reconstitution led to four types of chimeric mice(Donor bone marrow genotype recipient genotype):Wtwt, kowt, wtko, and koko.After cisplatin treatment, the wt recipients(Wtwt and kowt)Maintained their capacity for tnf production, whether wt or tnf ko bone marrow was reconstituted.In sharp contrast, tnf production was diminished in the tnfdeficient recipients, regardless of wt or ko bone marrow reconstitution.Thus, cisplatininduced tnf production in the chimeric models was determined by the genetic background of the recipient and not by beats by dre uk the donor bone marrow.These are remarkable findings, which suggest strongly that tnf is produced locally by resident cells of the kidneys, rather than by bone marrowderived immune cells that infiltrate the organ during cisplatin nephrotoxicity.Notably, wtwt and kowt chimeras developed severe kidney injury and renal failure after cisplatin treatment, whereas wtko and koko chimeras did not.This observation, although not surprising or particularly novel in view of the demonstrated involvement of tnf in cisplatin nephrotoxicity, indicates that tnf produced by the kidneys has an important pathogenic role. In addition to having an elegant experimental design involving chimeric models, the study by reeves and colleagues5 was also very carefully controlled.By transplantation of green fluorescent protein(Gfp)Labeled bone marrow from gfp transgenic mice, they demonstrated a high degree of chimerism in the mouse models.By twocolor flow cytometry, they showed that bone marrow transplantation did not alter the percentage distribution of leukocyte subtypes.They further demonstrated that circulating immune cells derived from transplanted bone marrow retained their ability to produce tnf upon stimulation by phorbol esters and ionomycin, known activators of leukocytes.These are critical controls, which indicate that the lack of tnf production by transplanted immune cells during cisplatin nephrotoxicity is not due to their faulty behavior, further supporting the conclusion that tnf is produced by resident kidney cells rather than bone marrowderived immune cells. Although negating a role of bone marrowderived immune cells in tnf production, the study by reeves and colleagues5 does not exclude the involvement of these cells in cisplatin nephrotoxicity.Recent work by rabb and colleagues6 demonstrated that, as compared with wildtype animals, t celldeficient mice were more resistant to cisplatin nephrotoxicity.Notably, reconstitution of tcells into these animals partially restored their sensitivity to cisplatin injury.6 Thus, immune cells, particularly the infiltrating Tcells, contribute to the development of renal pathology during cisplatin treatment.Intriguingly, rabb and colleagues also demonstrated that btsbydrdreoutletuk the production of proinflammatory cytokines, including tnf, was attenuated in t celldeficient mice, suggesting a role for t cells in triggering inflammation and tnf productionDuring cisplatin nephrotoxicity.6 Apparently, there is a discrepancy between the study by Reeves and colleagues and the study by Rabb's group:The former indicates tnf production by resident kidney cells, 5 whereas the latter suggests the involvement of infiltrating t cells.6 How can these findings be reconciled?One possibility is that, although tnf is produced mainly by resident kidney cells, infiltrating t cells may have a regulatory or stimulatory role.This scenario is supported by the observation that tcell infiltration occurs very early(Within hours)During cisplatin nephrotoxicity.6 Is there indeed a functional interaction between infiltrating T cells and resident kidney cells that leads to TNF production?How do t cells regulate tnf production in kidney cells?Do they secrete cytokines to prime these cells?What specific cytokines do they produce?These are important questions for investigation in the future. DeSpite the evidence for Tnf production by reSident kidney cellS, the exact identity of the reSponSible cell type(S)Has yet to be determined.In the kidneys, mesangial cells, glomerular cells, endothelial cells, and renal tubular cells are all capable of producing Tnf in response to a variety of stimuli.Reeves and colleagues showed recently that cisplatin treatment induced modest Tnf production in cultured proximal tubular cells, which involved gene transcription and mrna stabilization.7 Interestingly, in combination with endotoxins, cisplatin dramatically increases Tnf production and secretion.8 Tnf production following the combinatorial treatment seems to involve an intriguing regulation of protein translation via p38 mitogenactivated protein kinase and the translation initiation actor eIF4E.8 These novel findings suggest that renal tubular cells contribute to Tnf production during cisplatin nephrotoxicity and related pathological conditions.Certainly, this inference needs to be further established in vivo, ideally with the use of tubular cellspecific Tnf knockout models.If it is proven to be true in the kidneys, then the same tubular cells are producing a noxious molecule(Tnf)To insult themselves. Why iS it important to identify the cellS that produce tnf during ciSplatin nephrotoxicity?FirSt, thiS iS an eSSential Step toward a fundamental underStanding of tnf production and inflammation under the pathological condition.Without knowing what cellS are producing tnf, it will be very difficult, if not impoSSible, to gain further inSightS into the underlying molecular mechaniSmS.Second, many cell typeS are capable of producing tnf, and the Signaling pathwayS regulating tnf production in variouS cellS can be quite different.AS a reSult, identification of the tnfproducing cell type(S)May focus our effort on specific pathways in these cells for renoprotection during cisplatin treatment. How, then, is tnf involved in cisplatin nephrotoxicity?As a pleiotropic cytokine, tnf induces a variety of cellular responses ranging from inflammation to cell death.In a given cell, there are two types of tnf receptors, tnfr1 and tnfr2.Binding of the receptors activates distinct, but not mutually exclusive, signaling cascades.Notably, tnfr1 contains a conserved 'death domain, ' which, upon tnf ligation, can trigger the formation of a caspaseactivation complex, leading to apoptosis.In contrast, tnfr2 does not have the 'death domain' and therefore may not be directly involved in the initiation of apoptosis.During cisplatininduced nephrotoxicity, renal tubular cells undergo both necrotic and apoptotic cell death.Several years ago, tsuruya and colleagues showed that proximal tubular cells isolated from tnfr1deficient mice were more resistant to cisplatininduced caspase activation and apoptosis, suggesting the involvement of tnf signaling in tubularcell apoptosis under the experimental condition.9 On the other hand, Reeves and colleagues demonstrated the amelioration of cell death in TNFR2deficient mice after cisplatin treatment.10 Importantly, this and subsequent studies indicate that a major role of TNF is to stimulate the production of proinflammatory factors and recruit inflammatory cells.Consistent with this view, infiltration of leukocytes into the kidneys is reduced in wtko and koko chimeric mice, suggesting that tnf produced by resident kidney cells is, indeed, critically important in the inflammatory response.5 Thus TNF may trigger tubularcell death and tissue damage directly via TNFR1 as well as indirectly by mounting a robust inflammatory response via TNFR2(Figure 1).Nevertheless, while emphasizing the role of tnf in our discussion, it is important to recognize that cisplatin nephrotoxicity is a multifactorial process.Thus, although tnf is a significant contributing factor to the pathogenesis, it is unlikely to be the only one.Accordingly, pharmacological or genetic suppression of tnf and its signaling affords significant, but not complete, renoprotection during cisplatin nephrotoxicity.3, 5, 9, 10 A fascinating area for future study is to decipher how the multiple pathways or mechanisms are integrated to orchestrate a remarkable renal pathology. Full figure and beats by dre uk store legend(99K) Can we inhibit tnf to protect the kidneys from cisplatin injury?The answer is a sound yes, as demonstrated clearly by reeves and colleagues.3, 5, 10 However, it is still not clear whether inhibition of TNF is an effective strategy for renoprotection during cisplatinbased cancer therapy.An ideal approach for renoprotection during chemotherapy would prevent cell injury and death in the kidneys, yet preserve cell killing in tumors or cancers.Unfortunately, normal tissues(Including the kidneys)And cancer cells share many of the mechanisms of cell death in response to cytotoxic insults.It is unclear whether tnf mediates cisplatininduced cytotoxicity in cancers and whether inhibition of tnf will diminish the chemotherapeutic effects of cisplatin.Investigation in these areas may ultimately lead to the development of tnftargeted strategies for renoprotection during cisplatin therapy.

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