Insulin-like growth factor-1 (IGF-1) and growth hormone (GH) in immunity and inflammation

Heemskerk, V.H.; Daemen, M.A.R.C.; Buurman, Wim A.

doi:10.1016/s1359-6101(98)00022-7

Cited by 159 publications

(126 citation statements)

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“…6,23 Although epidemiological and experimental studies indicate that IGF-I activates cancer-related pathways, an association between IGF-I and breast cancer outcome has not been reported, and very few studies attempted to link serum IGF-I to pathway activation in human tissue specimens. We hypothesized that IGF-I may induce low-level tissue inflammation 24,25,44 and activate the Akt pathway. We did not observe an association between serum IGF-I concentrations and markers of inflammation in breast tumors, but found that serum IGF-I and the IGF-I/IGFBP3 ratio, a measure for bioavailable IGF-I, were associated with Akt pathway activation and predicted Akt phosphorylation at Thr308 in human breast tumors.…”

Section: Discussionmentioning

confidence: 99%

“…Serum IGF-I is a breast cancer risk factor that may enhance tissue inflammation. [23][24][25][26] We examined immunohistochemically the phosphorylation of Akt, BAD and caspase-9 in relation to nitric oxide synthase-2 (NOS2) and COX2 expression, tumor phagocyte density, and serum IGF-I. We also assessed the relationship between serum IGF-I and tissue inflammation, and examined possible interactions between these markers and the tumor Akt phosphorylation status in breast cancer survival.…”

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confidence: 99%

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Inflammation and IGF‐I activate the Akt pathway in breast cancer

Prueitt

Boersma

Howe

et al. 2006

Intl Journal of Cancer

111

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Akt signaling may promote breast cancer progression and poor disease outcome. We hypothesized that serum insulin-like growth factor I (IGF-I) and a proinflammatory tumor environment induce phosphorylation of Akt and downstream targets of Akt in breast cancer. We studied the relationship between Akt pathway activation, IGF-I and markers of inflammation, e.g., nitric oxide synthase-2 (NOS2), cyclooxygenase-2 (COX2) and tumor phagocyte density, in 248 breast tumors. We also examined the association of Akt phosphorylation with breast cancer survival. We observed that phosphorylation of Akt, BAD and caspase-9 correlated strongly with the expression of the 2 proinflammatory enzymes, NOS2 and COX2, in breast tumors (p < 0.001; Spearman rank correlation). Both NOS2 and COX2 expression were independently associated with Akt phosphorylation in the multivariate analysis. Serum IGF-I concentrations and the IGF-I/IGFBP3 ratio correlated with Akt phosphorylation at Thr308 and Ser473 in breast tumors (p 0.05; Spearman rank correlation). The association with Akt phosphorylation at Thr308 remained statistically significant in the multivariate analysis. Akt pathway activation was not associated with overall survival in the unstratified analysis, but we observed a statistical interaction between Akt phosphorylation and tumor phagocyte density on breast cancer survival (p interaction < 0.05). We further corroborated our findings in cell culture models by demonstrating that ANA-1 macrophages, nitric oxide and prostaglandin E 2 induce Akt phosphorylation in human breast cancer cells. In summary, a proinflammatory environment was found to activate the Akt pathway in breast cancer, and may modify the association between the Akt phosphorylation status and breast cancer survival. ' 2006 Wiley-Liss, Inc.Key words: breast cancer; Akt; inflammation; insulin-like growth factor; survival The Akt family of serine/threonine protein kinases are putative oncogenes that enhance the survival of various cell types. 1,2 The 3 closely related Akt isoforms induce cell proliferation and soft agar growth, and disrupt the acinar architecture of human mammary cells, but do not induce transformation by themselves. 3-5 Akt activation requires 2 critical phosphorylation steps at Thr308 and Ser473. The phosphorylation is induced by ligand-mediated activation of growth factor receptors and receptor tyrosine kinases. Insulin-like growth factor I (IGF-I), insulin and the epidermal growth factor are ligands that activate Akt through the receptormediated pathway. 1,6 The phosphorylation of membrane-bound Akt establishes the full Akt kinase activity and induces Akt translocation into the cytosol and nucleus. 7-10 Activated Akt phosphorylates a number of downstream targets such as BAD, caspase-9, p21, p27, GSK3b, Mdm2, mTOR, IKKa and others. 1,11,12 The phosphorylation of BAD and caspase-9 blocks the apoptotic activity of the 2 proteins and raises the threshold for apoptosis. [13][14][15] Thus, tumors that show a high phosphorylation of BAD and caspase-9 may have a ...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Inflammation and IGF‐I activate the Akt pathway in breast cancer

Prueitt

Boersma

Howe

et al. 2006

Intl Journal of Cancer

111

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“…In general, IGF-I and insulin have broad activities in the mammalian innate immune system (reviewed in [23]), and these effects are dose-dependent. Normal circulating levels of mammalian IGF-I range from 0.8 -1.0 μg/ml (0.11 -0.13 μM; [24]) and those of insulin arẽ 0.4 ng/ml (6.7 x 10 -5 μM or 0.067 nM; [25]).…”

Section: The Isc Innate Immunity and Aging In Mammalsmentioning

confidence: 99%

“…The authors also showed that fecundity was reduced in immune-activated females via the "immune deficiency" or imd pathway, suggesting that maximum reproduction occurs in young flies, perhaps as a benefit from increased regulation of the immune response [17]. In general, IGF-I and insulin have broad activities in the mammalian innate immune system (reviewed in [23]), and these effects are dose-dependent. Normal circulating levels of mammalian IGF-I range from 0.8 -1.0 μg/ml (0.11 -0.13 μM; [24]) and those of insulin arẽ 0.4 ng/ml (6.7 x 10 -5 μM or 0.067 nM; [25]).…”

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confidence: 99%

The insulin signaling cascade from nematodes to mammals: Insights into innate immunity of Anopheles mosquitoes to malaria parasite infection

Luckhart

Riehle

2007

Developmental & Comparative Immunology

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As revealed over the past twenty years, the insulin signaling cascade plays a central role in regulating immune and oxidative stress responses that affect the life spans of mammals and two model invertebrates, the nematode Caenorhabitis elegans and the fruit fly Drosophila melanogaster. In mosquitoes, insulin signaling regulates key steps in egg maturation and immunity and likely affects aging, although the latter has yet to be examined in detail. Reproduction, immunity and aging critically influence the capacity of mosquitoes to effectively transmit malaria parasites. Current work has demonstrated that molecules from the invading parasite and the blood meal elicit functional responses in female mosquitoes that are regulated through the insulin signaling pathway or by crosstalk with interacting pathways. Defining the details of these regulatory interactions presents significant challenges for future research, but will increase our understanding of mosquito/malaria parasite transmission and of the conservation of insulin signaling as a key regulatory nexus in animal biology. Keywordsinsulin; Anopheles; Plasmodium; mosquito; malaria; aging; oxidative stress; innate immunity; nitric oxide; transforming growth factor; β In all well-studied metazoans, metabolism, growth, and longevity are coordinately regulated via a nexus that involves signaling cascades activated by insulin and insulin-like growth factors (IGF). Although these pathways differ in downstream physiological effects and some of their signaling proteins, the proteins themselves and their scaffolding interactions are largely conserved among model organisms ( Fig. 1), particularly in the nematode Caenorhabditis elegans, the fruit fly Drosophila melanogaster, and the mouse Mus musculus. This review will examine our current understanding of how the insulin and IGF signaling cascades (ISC) regulate immunity in these diverse model organisms. In addition, we will explore how recent Correspondence to: Shirley Luckhart. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errorsmaybe discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Key targets of daf-16 regulation include genes for mitochondrial manganese superoxide dismutase (MnSOD) and glutathione S-transferase, which are closely linked to aging in C. elegans and other organisms, and genes for numerous C-type lectins, which play critical roles in cell adhesion and pathogen recognition [5]. Downregulation of these gene targets in daf-16 mutants would be predicted to enhance oxidative stress, which has been linked directly to aging in C. elegans [6,7], and decrease pathogen recognition [8]. Conversely, rescue of downregulated MnSOD...

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“…Nevertheless, it is the major determinant of the free IGF-I concentration [1], and the only IGFBP that exhibits tightly regulated expression [3]. While other IGFBPs are expressed in various peripheral tissues, IGFBP-1 is produced primarily by the liver, and under basal conditions insulin is the primary regulator of its transcription [3]. However, IGFBP-1 production is potently upregulated in humans and rodents in response to sepsis [4], endotoxin injection [5,6] and other inflammatory stimuli.…”

Section: Introductionmentioning

confidence: 99%

Regulation of insulin-like growth factor binding protein-1 expression during aging

Rutkute

Nikolova‐Karakashian

2007

Biochemical and Biophysical Research Communications

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Insulin-like growth factor (IGF) binding protein-1 (IGFBP-1) is primarily produced in the liver during inflammation and regulates biological activities of IGF-I. Here we demonstrate that interleukin-1β (IL-1β) stimulates IGFBP-1 mRNA production in a dose-dependent manner in hepatocytes from Fisher 344 rats. Employment of c-Jun N-terminal kinase (JNK) inhibitor SP600125 resulted in 3-fold reduction of IGFBP-1 mRNA and protein levels, indicating that IL-1β-induced IGFBP-1 production is mediated through JNK activation. We further show that hepatocytes from aged rats (20-22 mo), as compared to young (3-4 mo), exhibit up to 2-fold higher levels of IGFBP-1 in response to IL-1β. IL-1β-induced phosphorylation of JNK was also significantly higher in aged hepatocytes, and SP600125 treatment eliminated age-related differences in IGFBP-1 mRNA production. Moreover, glutathione depletion in hepatocytes from young rats potently activated JNK, as well as increased IL-1β-induced IGFBP-1 mRNA levels, suggesting that age-related oxidative stress underlies the upregulated JNK activation and IGFBP-1 expression.

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Insulin-like growth factor-1 (IGF-1) and growth hormone (GH) in immunity and inflammation

Cited by 159 publications

References 91 publications

Inflammation and IGF‐I activate the Akt pathway in breast cancer

Inflammation and IGF‐I activate the Akt pathway in breast cancer

The insulin signaling cascade from nematodes to mammals: Insights into innate immunity of Anopheles mosquitoes to malaria parasite infection

Regulation of insulin-like growth factor binding protein-1 expression during aging

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