Transgenic overexpression of interleukin-8 in mouse liver protects against galactosamine/endotoxin toxicity

Hanson, Jennifer C.; Bostick, Michele K.; Campe, Carson B.; Kodali, Pratima; Lee, Gene; Yan, Jenny; Maher, Jacquelyn J.

doi:10.1016/j.jhep.2005.06.022

Cited by 14 publications

(10 citation statements)

References 62 publications

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“…These mice have circulating neutrophilia and impaired chemotaxis to intraperitoneal thioglycollate, but organ histology and function have been reported as normal [25], with no description of a bone phenotype. Genotype was confirmed by the measurement of human IL-8 in mouse serum.…”

Section: Methodsmentioning

confidence: 99%

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Circulating interleukin-8 levels explain breast cancer osteolysis in mice and humans

Kamalakar

Bendre

Washam

et al. 2014

Bone

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Skeletal metastases of breast cancer and subsequent osteolysis connote a dramatic change in the prognosis for the patient and significantly increase the morbidity associated with disease. The cytokine Interleukin 8 (IL-8/CXCL8) is able to directly stimulate osteoclastogenesis and bone resorption in mouse models of breast cancer bone metastasis. In this study, we determined whether circulating levels of IL-8 were associated with increased bone resorption and breast cancer bone metastasis in patients, and investigated IL-8 action in vitro and in vivo in mice. Using breast cancer patient plasma (36 patients), we identified significantly elevated IL-8 levels in bone metastasis patients compared with patients lacking bone metastasis (p<0.05), as well as a correlation between plasma IL-8 and increased bone resorption (p<0.05), as measured by NTx levels. In a total of 22 ER+ and 15 ER− primary invasive ductal carcinomas, all cases examined stained positive for IL-8 expression. In vitro, human MDA-MB-231 and MDA-MET breast cancer cell lines secrete two distinct IL-8 isoforms, both of which were found to stimulate osteoclastogenesis. However, the more osteolytic MDA-MET–derived full length IL-8(1–77) had significantly higher potency than the non-osteolytic MDA-MB-231-derived IL-8(6–77), via the CXCR1 receptor. MDA-MET breast cancer cells were injected into the tibia of nude mice and 7 days later treated daily with a neutralizing IL-8 monoclonal antibody. All tumor-injected mice receiving no antibody developed large osteolytic bone tumors, whereas 83% of the IL-8 antibody-treated mice had no evidence of tumor at the end of 28 days and had significantly increased survival. The pro-osteoclastogenic activity of IL-8 in vivo was confirmed when transgenic mice expressing human IL-8 were examined and found to have a profound osteopenic phenotype, with elevated bone resorption and inherently low bone mass. Collectively, these data suggest that IL-8 plays an important role in breast cancer osteolysis and that anti-IL-8 therapy may be useful in the treatment of the skeletal related events associated with breast cancer.

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Section: Methodsmentioning

confidence: 99%

“…For bone phenotype assessment of IL-8 transgenic mice, 10 male and 6 female IL-8 transgenic mice (4 months) and 9 male and 6 female WT littermate controls were examined. Serum IL-8 levels were measured to determine the genotype of the mice [25], and blood was drawn and serum prepared for serum bone biochemical marker analyses.…”

Section: Methodsmentioning

confidence: 99%

Circulating interleukin-8 levels explain breast cancer osteolysis in mice and humans

Kamalakar

Bendre

Washam

et al. 2014

Bone

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“…Chronic overexpression of IL-8 in transgenic mice increases the number of neutophils in sinusoids without transmigration. In fact, IL-8 overexpression actually attenuates TNF-induced hepatocellular apoptosis, which correlated with activation of phosphatidylinositol (PI)3-kinase/AKT survival pathways (7). On the other hand, high doses of MIP-2 and other ELRcontaining CXC chemokines can also protect against druginduced liver cell injury by triggering mitosis and liver regeneration (10).…”

Section: Signals For Neutrophil Extravasationmentioning

confidence: 99%

Mechanisms of Liver Injury. II. Mechanisms of neutrophil-induced liver cell injury during hepatic ischemia-reperfusion and other acute inflammatory conditions

Jaeschke¹

2006

American Journal of Physiology-Gastrointestinal and Liver Physi

424

389

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“…CXCL8 administration protects mice against concanavalin A-induced hepatitis by inhibiting apoptosis and growth arrest of hepatocytes (26). Similar protective mechanisms have been observed in mice with hepatic overexpression of the CXCL8 ortholog KC where liver injury was induced by galactosamine and endotoxin (8). KC is upregulated by the hepatoprotective cytokine interleukin (IL)-6 via the activation of the IL6-gp130-STAT3 pathway, and recombinant KC reduces serum aminotransferase levels in mice with concanavalin A-mediated liver damage (14).…”

mentioning

confidence: 57%

Adiponectin-stimulated CXCL8 release in primary human hepatocytes is regulated by ERK1/ERK2, p38 MAPK, NF-κB, and STAT3 signaling pathways

Wanninger¹,

Neumeier²,

Weigert³

et al. 2009

American Journal of Physiology-Gastrointestinal and Liver Physi

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Adiponectin is believed to exert hepatoprotective effects and induces CXCL8, a chemokine that functions as a survival factor, in vascular cells. In the current study, it is demonstrated that adiponectin also induces CXCL8 expression in primary human hepatocytes but not in hepatocellular carcinoma cell lines. Knock down of the adiponectin receptor (AdipoR) 1 or AdipoR2 by small-interfering RNA indicates that AdipoR1 is involved in adiponectin-stimulated CXCL8 release. Adiponectin activates nuclear factor (NF)-kappaB in primary hepatocytes and pharmacological inhibition of NF-kappaB, the p38 mitogen-activated protein kinase, and extracellular signal-regulated kinase (ERK) 1/ERK2 reduces adiponectin-mediated CXCL8 secretion. Furthermore, adiponectin also activates STAT3 involved in interleukin (IL)-6 and leptin-mediated CXCL8 induction in primary hepatocytes. Inhibition of JAK2 by AG-490 does not abolish adiponectin-stimulated CXCL8, indicating that this kinase is not involved. Pretreatment of primary cells with "STAT3 Inhibitor VI," however, elevates hepatocytic CXCL8 secretion, demonstrating that STAT3 is a negative regulator of CXCL8 in these cells. In accordance with this assumption, IL-6, a well-characterized activator of STAT3, reduces hepatocytic CXCL8. Therefore, adiponectin-stimulated induction of CXCL8 seems to be tightly controlled in primary human hepatocytes, whereas neither NF-kappaB, STAT3, nor CXCL8 are influenced in hepatocytic cell lines. CXCL8 is a survival factor, and its upregulation by adiponectin may contribute to the hepatoprotective effects of this adipokine.

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Transgenic overexpression of interleukin-8 in mouse liver protects against galactosamine/endotoxin toxicity

Cited by 14 publications

References 62 publications

Circulating interleukin-8 levels explain breast cancer osteolysis in mice and humans

Circulating interleukin-8 levels explain breast cancer osteolysis in mice and humans

Mechanisms of Liver Injury. II. Mechanisms of neutrophil-induced liver cell injury during hepatic ischemia-reperfusion and other acute inflammatory conditions

Adiponectin-stimulated CXCL8 release in primary human hepatocytes is regulated by ERK1/ERK2, p38 MAPK, NF-κB, and STAT3 signaling pathways

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