Iron overload impairs pro‐inflammatory cytokine responses by Kupffer cells

Olynyk, John K.; Clarke, Sharon L

doi:10.1046/j.1440-1746.2001.02456.x

Cited by 36 publications

(26 citation statements)

References 52 publications

(59 reference statements)

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“…It is possible that secretion of a variety of cytokines by adipocytes and inflammatory macrophages may have modulated carcinogenesis after iron overload. 57 It also remains elusive whether mesothelioma truly originates from surface mesothelial cells, as mesothelial cells and lymphatic cells are seamlessly connected in the parietal pleura. 58 In expression microarrays, it is important to choose appropriate control samples.…”

Section: Discussionmentioning

confidence: 99%

Homozygous deletion of CDKN2A/2B is a hallmark of iron-induced high-grade rat mesothelioma

Akatsuka

Yamashita

et al. 2010

Laboratory Investigation

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In humans, mesothelioma has been linked to asbestos exposure, especially crocidolite and amosite asbestos, which contain high amounts of iron. Previously, we established a rat model of iron-induced peritoneal mesothelioma with repeated intraperitoneal injections of iron saccharate and an iron chelator, nitrilotriacetate. Here, we analyze these mesotheliomas using array-based comparative genomic hybridization (aCGH) and gene expression profiling by microarray. Mesotheliomas were classified into two distinct types after pathologic evaluation by immunohistochemistry. The major type, epithelioid mesothelioma (EM), originated in the vicinity of tunica vaginalis testis, expanded into the upper peritoneal cavity and exhibited papillary growth and intense podoplanin immunopositivity. The minor type, sarcomatoid mesothelioma (SM), originated from intraperitoneal organs and exhibited prominent invasiveness and lethality. Both mesothelioma types showed male preponderance. SMs revealed massive genomic alterations after aCGH analysis, including homozygous deletion of CDKN2A/2B and amplification of ERBB2 containing region, whereas EMs showed less genomic alterations. Uromodulin was highly expressed in most of the cases. After 4-week treatment, iron deposition in the mesothelia was observed with 8-hydroxy-2 0 -deoxyguanosine formation. These results not only show two distinct molecular pathways for iron-induced peritoneal mesothelioma, but also support the hypothesis that oxidative stress by iron overload is a major cause of CDKN2A/2B homozygous deletion.

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Section: Discussionmentioning

confidence: 99%

Homozygous deletion of CDKN2A/2B is a hallmark of iron-induced high-grade rat mesothelioma

Akatsuka

Yamashita

et al. 2010

Laboratory Investigation

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“…Furthermore, apoptosis, which can follow the mitochondrial swelling associated with permeability transition, is often accompanied by a transient increase in R123 fluorescence (38). Previous research has shown that iron deficiency and excess can also impair immune function (41,42) and neutrophil activation and metabolism (43,44). These findings strongly suggest that both iron deficiency and moderate excess are detrimental to mitochondria.…”

Section: Figmentioning

confidence: 99%

Iron deficiency and iron excess damage mitochondria and mitochondrial DNA in rats

Walter

Knutson

Paler-Martı́nez

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

304

182

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Approximately two billion people, mainly women and children, are iron deficient. Two studies examined the effects of iron deficiency and supplementation on rats. In study 1, mitochondrial functional parameters and mitochondrial DNA (mtDNA) damage were assayed in iron-deficient (<5 g͞day) and iron-normal (800 g͞day) rats and in both groups after daily high-iron supplementation (8,000 g͞day) for 34 days. This dose is equivalent to the daily dose commonly given to iron-deficient humans. Iron-deficient rats had lower liver mitochondrial respiratory control ratios and increased levels of oxidants in polymorphonuclear-leukocytes, as assayed by dichlorofluorescein (P < 0.05). Rhodamine 123 fluorescence of polymorphonuclear-leukocytes also increased (P < 0.05). Lowered respiratory control ratios were found in daily high-iron-supplemented rats regardless of the previous iron status (P < 0.05). mtDNA damage was observed in both iron-deficient rats and rats receiving daily high-iron supplementation, compared with ironnormal rats (P < 0.05). Study 2 compared iron-deficient rats given high doses of iron (8,000 g) either daily or every third day and found that rats given iron supplements every third day had less mtDNA damage on the second and third day after the last dose compared to daily high iron doses. Both inadequate and excessive iron (10 ؋ nutritional need) cause significant mitochondrial malfunction. Although excess iron has been known to cause oxidative damage, the observation of oxidant-induced damage to mitochondria from iron deficiency has been unrecognized previously. Untreated iron deficiency, as well as excessive-iron supplementation, are deleterious and emphasize the importance of maintaining optimal iron intake.

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“…First, iron is known to affect cellmediated immune response (14). Excessive iron load in macrophages reduces their functions, including phagocytosis, respiratory burst, and cytokine expression (15)(16)(17), the effects likely mediated by iron-mediated toxicity (18). On the other hand, at non-toxic concentrations, iron promotes macrophage differentiation (19) and functions, including anti-microbial effects (20) and TNF-mediated cytotoxicity (21).…”

mentioning

confidence: 99%

Signaling Role of Intracellular Iron in NF-κB Activation

Xiong

She

Takeuchi

et al. 2003

Journal of Biological Chemistry

159

122

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Iron overload impairs pro‐inflammatory cytokine responses by Kupffer cells

Abstract: Deposition of iron in Kupffer cells in chronic dietary iron overload results in an impaired pro-inflammatory cytokine response to lipopolysaccharide. Our observations may have relevance to the altered immune function observed in chronic iron-overload syndromes.

Cited by 36 publications

References 52 publications

Homozygous deletion of CDKN2A/2B is a hallmark of iron-induced high-grade rat mesothelioma

Homozygous deletion of CDKN2A/2B is a hallmark of iron-induced high-grade rat mesothelioma

Iron deficiency and iron excess damage mitochondria and mitochondrial DNA in rats

Signaling Role of Intracellular Iron in NF-κB Activation

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