Cytokines regulate IGF binding proteins in the CNS

doi:10.1016/0955-2235(95)00035-6

Progress in Growth Factor Research

Volume 6, Issues 2–4, 1995, Pages 181-187

Progress in Growth F...

https://doi.org/10.1016/0955-2235(95)00035-6 Get rights and content

Abstract

Growth factor induction is a major component of the response to central nervous system trauma. The insulin-like growth factors (IGFs) and IGF binding proteins (IGFBPs) are among the molecules induced by injury that have demonstrated neuroprotective actions. Induction of IGFBPs 2, 3, 4 and 5 have been documented following injury and are hypothesized to function in transport or localization of the IGFs to injured cells. It is unclear what factors lead to induction of these molecules following trauma, however, several cytokines including ciliary neurotrophic factor (CNTF) and interleukin-1β (IL-1β) have been described as major injury signals and can induce aspects of reactive gliosis. To establish whether these cytokines also are responsible for inducing the IGFBPs following CNS injury, we injected CNTF or IL-1β intracerebrally into the neocortex of adult rats and measured changes in mRNA expression for the IGFBPs. IGFBP-2 mRNA showed a dramatic increase by 24–48 h following either CNTF or IL-1β injection as compared with the contralateral side injected with heat-inactivated cytokine. Neither CNTF nor IL-1β caused alterations in BP3 or BP5. Levels of BP4 and BP6 mRNAs also were unchanged following CNTF injection. These results suggest that IGFBP2 is uniquely regulated among the IGFBPs in the CNS and is induced by cytokines that signal CNS injury.

References (19)

J.K. Relton et al.
Interleukin-1 receptor antagonist inhibits ischaemic and excitotoxic neuronal damage in the rat
Brain Res Bull
(1992)
B. Schöbitz et al.
Gene expression and function of interleukin 1, interleukin 6 and tumor necrosis factor in the brain
Prog Neurobiol
(1994)
P. Gluckman et al.
A role for IGF-1 in the rescue of CNS neurons following hypoxic-ischemic injury
Biochem Biophys Res Commun
(1992)
A. Logan et al.
Growth factors in CNS repair and regeneration
Prog Growth Factor Res
(1994)
W.-H. Lee et al.
Insulin-like growth factors in the response to cerebral ischemia
Mol Cell Neuro
(1992)
J.T. Henderson et al.
Localization of CNTF immunoreactivity to neurons and astroglia in the CNS
Mol Brain Res
(1994)
A.L. Brown et al.
Nucleotide sequence and expression of a cDNA clone encoding a fetal rat binding protein for insulin-like growth factors
J Biol Chem
(1989)
S. Shimasaki et al.
Complementary DNA structure of the high molecular weight rat insulin-like growth factor binding protein (IGFBP3) and tissue distribution of its mRNA
Biochem Biophys Res Commun
(1989)
P.L. James et al.
A highly conserved insulin-like growth factor binding protein (IGFBP-5) is expressed during myoblast differentiation
J Biol Chem
(1993)

There are more references available in the full text version of this article.

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Citation Excerpt :
However, intravenous injection of E. coli endotoxin into healthy humans elicits an increase in IGFBP-2 over several hours [27,28]. Furthermore, IGFBP-2 mRNA shows a dramatic increase by 24–48 h following either CNTF or IL-1 beta injection in a rat model of central nervous system injury [29]. The role of IGFBP-2 in the pathogenesis of HUS is still unknown, but IGFBP-2 might have pleiotropic effects through the interactions with other cytokines.
Proinflammatory cytokines are related to the pathogenesis of enterohemorrhagic Escherichia coli infection and hemolytic-uremic syndrome (HUS). We employed an antibody array that simultaneously detects 174 serum cytokines. We identified five serum biomarkers, namely insulin growth factor-binding protein-2, angiopoietin-2, soluble interleukin-6 receptor, soluble tumor necrosis factor receptor type II, and matrix metalloprotease protein-3 whose levels increased with the development of HUS. Furthermore, the levels of these cytokines were significantly increased in severe HUS compared with mild HUS. These cytokines might play an important role in the pathogenesis of HUS and may also be used to predict the severity of HUS.
Ciliary neurotrophic factor activates spinal cord astrocytes, stimulating their production and release of fibroblast growth factor-2, to increase motor neuron survival
2002, Experimental Neurology
At focal CNS injury sites, several cytokines accumulate, including ciliary neurotrophic factor (CNTF) and interleukin-1β (IL-1β). Additionally, the CNTF alpha receptor is induced on astrocytes, establishing an autocrine/paracrine loop. How astrocyte function is altered as a result of CNTF stimulation remains incompletely characterized. Here, we demonstrate that direct injection of CNTF into the spinal cord increases GFAP expression and astroglial size and that primary cultures of spinal cord astrocytes treated with CNTF, IL-1β, or leukemia inhibitory factor exhibit nuclear hypertrophy comparable to that observed in vivo. Using a coculture bioassay, we further demonstrate that CNTF treatment of astrocytes increases their ability to support ChAT⁺ ventral spinal cord neurons (presumably motor neurons) more than twofold compared with untreated astrocytes. Also, the complexity of neurites was significantly increased in neurons cultured with CNTF-treated astrocytes compared with untreated astrocytes. RT–PCR analysis demonstrated that CNTF increased levels of FGF-2 and nerve growth factor (NGF) mRNA and that IL-1β increased NGF and hepatocyte growth factor mRNA levels. Furthermore, both CNTF and IL-1β stimulated the release of FGF-2 from cultured spinal cord astrocytes. These findings demonstrate that cytokine-activated astrocytes better support CNS neuron survival via the production of neurotrophic molecules. We also show that CNTF synergizes with FGF-2, but not epidermal growth factor, to promote DNA synthesis in spinal cord astrocyte cultures. The significance of these findings is discussed by presenting a new model depicting the sequential activation of astrocytes by cytokines and growth factors in the context of CNS injury and repair.
Depolarization induces insulin-like growth factor binding protein-2 expression in vivo via NMDA receptor stimulation
2001, Growth Hormone and IGF Research
The effect of depolarization and N -methyl- $D$ -aspartate (NMDA) receptor blockade on insulin-like growth factor-I (IGF-I), IGF binding protein-2 (IGFBP-2) and IGFBP-4 expression was analysed in vivo. Depolarization was induced in adult rat brains by applying 3 M KCl to the exposed cortex for 10 min. A subgroup of animals also received daily injections of MK-801. Four days after KCl exposure, the brains were analysed by in situ hybridization, immunohistochemistry and TUNEL. A significant upregulation of IGFBP-2 mRNA and protein was detected in astrocytes after KCl exposure This upregulation was reduced by MK-801 treatment. No alterations in IGF-I or IGFBP-4 mRNA levels were noted. We did not detect TUNEL positive cells, morphological signs of necrosis or apoptosis, or neuronal loss in the depolarized zone. Taken together, these findings indicate that upregulation of IGFBP-2 by depolarization is mediated by NMDA receptors, and, as no neuronal damage was detected, astrocytic NMDA receptors may be responsible for this upregulation.
Ciliary neurotrophic factor stimulates astroglial hypertrophy in vivo and in vitro
1998, Experimental Neurology
After insult or trauma, astrocytes become activated and endeavor to restore the brain's delicately balanced microenvironment. An index of their activated state is that they become enlarged or hypertrophic. Ciliary neurotrophic factor (CNTF), a member of the alpha helical family of cytokines, is synthesized by astrocytes and is generally regarded to be an autocrine and paracrine injury signal. To determine whether CNTF might be an endogenous signal that stimulates astrocyte hypertrophyin vivo,we intracerebrally injected 200 ng of recombinant human CNTF into the adult rat neocortex. To study the astrocytes their cytosol was stained with antibodies against S100β and their nuclei were stained with propidium iodide (PI). Fluorescent images of astrocytic nuclei and somas were acquired using a confocal laser-scanning microscope and their areas were measured using the NIH image software. Within 24 h of treatment, CNTF induced a volume increase of the somas and nuclei of protoplasmic and fibrous astrocytesin vivo,and this effect persisted for at least 48 h. To determine whether CNTF activates astrocytes directly, glial cultures were treated with CNTF (10 ng/ml) and were evaluated by measuring the area of PI stained nuclei. CNTF stimulation increased the size of both polygonal and process-bearing astroglia. Since our studiesin vivohave shown that CNTF induces other key aspects of gliosis (S. W. Levisonet al.,1996;Exp. Neurol.141,256), we conclude that CNTF is a powerful activator of astrocytes and that it is likely responsible for the persistent glial hypertrophy observed following injuries and diseases of the CNS.
The effect of insulin-like growth factors on brain myelination and their potential therapeutic application in myelination disorders
1997, European Journal of Paediatric Neurology
Degenerative disorders of the cerebral white matter, leukodystrophies and demyelination diseases, are characterized by the faulty formation or excessive breakdown of myelin. Insulin-like growth factors (IGFs) promote the proliferation of oligodendrocytes as well as their myelin synthesis. IGF-I overexpressing mice show a significant increase in brain weight associated with increased myelin content. In contrast, the brains of IGF-binding protein-1 transgenic mice show a dramatic decrease in myelination. Furthermore, IGFs and IGF-binding proteins are among the factors that are induced by brain injury and have neuroprotective effects. IGFs also induce neurite growth and survival, in particular in glial cells of the peripheral nervous system. In demyelinating diseases, IGF-I may be useful for reducing myelin breakdown and promoting myelin regeneration. These observations may lead to new therapeutic applications for IGFs, for example promoting remyelination or limiting damage following brain injury.
Acute exposure to CNTF in vivo induces multiple components of reactive gliosis
1996, Experimental Neurology
CNS trauma or disease induces a constellation of changes in the glia comprising the condition known as reactive gliosis. At present, little is known regarding the nature of the injury signals and the specific consequences of their actions. Ciliary neurotrophic factor (CNTF) induces acute phase proteins in liver and increases astrocytic glial fibrillary acidic protein (GFAP) bothin vitroandin vivo.The purpose of the present study was to establish whether CNTF induces other aspects of gliosis. Between 10 and 72 h after 100 ng of recombinant human CNTF was administered into the adult rat neocortex, alterations were observed in a region extending several millimeters in circumference from the injection site. Microglia in this region were more apparent and astrocytes were hypertrophic. Byin situhybridization, mRNAs for GFAP, vimentin, and clusterin were upregulated when compared to the control hemisphere (which received heat-inactivated CNTF). By immunocytochemistry, GFAP, vimentin, glutathione-S-transferase μ, S-100, and OX-42 were elevated by 48 h. By contrast, the oligodendroglial marker GST Yp, the neuronal markers MAP-2 and NSE, the intermediate filament nestin, and the stress protein αB-crystallin were unchanged. In addition, a greater than twofold increase in the number of proliferating cells was observed. Since CNTF induces swelling and multiple “gliotic” genes in astrocytes, increases microglial number, and stimulates cell proliferation, we conclude that CNTF is sufficient to induce multiple aspects of gliosis. These data are consistent with a model whereby CNTF (which is synthesized by astrocytes) would be released when the integrity of the astrocyte membrane is compromised, whereupon it would elicit an inflammatory response.

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Cytokines regulate IGF binding proteins in the CNS

Abstract

Brain Res Bull

Prog Neurobiol

Biochem Biophys Res Commun

Prog Growth Factor Res

Mol Cell Neuro

Mol Brain Res

J Biol Chem

Biochem Biophys Res Commun

J Biol Chem