Disease relevance of Cntf

• Soluble footpad extracts induced the same changes in NBFL neuroblastoma cells as LIF and CNTF, including increased vasoactive intestinal peptide mRNA, STAT3 dimerization, and DNA binding, and stimulation of transcription from the vasoactive intestinal peptide cytokine-responsive element [1].
• We hypothesize that CNTF released from destroyed beta-cells during the inflammatory islet lesion leading to IDDM may potentiate IL-1beta action on the beta-cells [2].
• IL-6 is related to ciliary neurotrophic factor (CNTF), a trophic factor for motoneurons, sensory dorsal root ganglion (DRG) neurons, and other neuronal subpopulations [3].
• CNTF expression was up-regulated from the day following ICH induction and reached a peak level at 5 to 14 days, with increased expression observed in brain tissue surrounding the hematoma lesion and white matter structures in association with astroglial proliferation [4].
• However, little is known about the expression of CNTF or that of its receptor (CNTFR-alpha) in cases of intracerebral hemorrhage (ICH) [4].

Psychiatry related information on Cntf

• Ciliary neurotrophic factor prevents behavioural deficits and striatal degeneration in rat and primate models of Huntington's disease [5].
• CNTF infusion prevented the occurrence of ischemia-induced learning disability in a dose-dependent manner in rats subjected to the Morris water maze task [6].

High impact information on Cntf

• Trophic effect of ciliary neurotrophic factor on denervated skeletal muscle [7].
• In vivo, administration of CNTF activates these receptors on skeletal muscle by inducing receptor phosphorylation and immediate-early gene responses [7].
• Adenoviral gene transfer of ciliary neurotrophic factor and brain-derived neurotrophic factor leads to long-term survival of axotomized motor neurons [8].
• The neurotrophic factors ciliary neurotrophic factor and brain-derived neurotrophic factor can prevent motor neuron cell death during development and after nerve lesion in neonatal rodents [8].
• Although CNTF is abundant in adult sciatic nerve, the mature protein lacks a signal sequence and is not secreted; therefore, it has been proposed to act as a lesion factor [9].

Chemical compound and disease context of Cntf

• Implantation of C6 glioma cells engineered to secrete CNTF either subcutaneously or into the peritoneal cavity of adult mice, or systemic injections of purified rat or human recombinant CNTF, resulted in a rapid syndrome of weight loss resulting in death over a period of 7-10 d [10].
• In this study, expression of an interfering mutant of SHP-2 in the neuroblastoma cell line NBFL increased CNTF induction of a vasoactive intestinal peptide (VIP) reporter gene, and in cultures of sympathetic neurons, it resulted in an up-regulation of endogenous VIP and substance P (SP) gene expression [11].
• Thus LIF and CNTF have similar effects on lipid metabolism; they join a growing list of cytokines that stimulate hepatic triglyceride secretion and may mediate the changes in lipid metabolism that accompany the acute phase response [12].
• In an initial series of experiments, unilateral injections of CNTF adenovirus were performed in rats 10, 30, or 90 d before a 5 d neurotoxic treatment with systemic 3-nitropropionic acid (3NP) [13].
• Pretreatment with phenylisopropyl adenosine, which inhibits lipolysis, partially inhibited LIF- and CNTF-induced hypertriglyceridemia [12].

Biological context of Cntf

• BDNF protein was rapidly upregulated within 24 hr after lesion, whereas CNTF protein upregulation was delayed reaching maximal levels by 3 d [14].
• Given the effects of a related family member (ciliary neurotrophic factor, CNTF) on neuronal cell survival, we studied the ability of CT-1 to promote cardiac myocyte survival and proliferation in vitro [15].
• We show that reintroduction of rat hippocampal neurons to rat hippocampal astrocytes in vitro leads to a time dependent downregulation in astrocytes of the neurotrophic factors CNTF, NGF, and neurotrophin 3 (NT-3) [14].
• CNTF induces raphe neuronal precursors to switch from a serotonergic to a cholinergic phenotype in vitro [16].
• In contrast, less than 10% of newborn NG neurons survived in the presence of LIF or CNTF, suggesting a loss in responsiveness to these factors during fetal development in vivo [17].

Anatomical context of Cntf

• These findings strongly suggest that increases in endogenous bFGF and/or CNTF play key roles in injury-induced photoreceptor rescue [18].
• Our data indicate that leukemia inhibitory factor (LIF) and ciliary neurotrophic factor (CNTF) cause sympathetic neurons to retract their dendrites in vitro, ultimately leading to an approximately 80% reduction in the size of the arbor [19].
• In addition, CNTFR3alpha inhibits the proliferation of the TF1 hematopoietic cell line triggered by CNTF plus soluble wild type CNTFRalpha but not by IL-6 or oncostatin M [20].
• Ciliary neurotrophic factor potentiates the beta-cell inhibitory effect of IL-1beta in rat pancreatic islets associated with increased nitric oxide synthesis and increased expression of inducible nitric oxide synthase [2].
• In conclusion, CNTF is constitutively expressed in pancreatic beta-cells and potentiates the beta-cell inhibitory effect of IL-1beta in association with increased iNOS expression and NO synthesis, an effect shared by IL-6 but not by beta-NGF [2].

Associations of Cntf with chemical compounds

• CNTF (20 ng/ml) potentiated IL-1beta-mediated (5-150 pg/ml) nitric oxide (NO) synthesis from neonatal Wistar rat islets by 31-116%, inhibition of accumulated insulin release by 34-49%, and inhibition insulin response to a 2-h glucose challenge by 31-36% [2].
• Positions 268 and 269 of CNTFRalpha appear to be critical for its interaction with gp130 and LIFRbeta, whereby alanine substitution of the residues at these positions results in antagonism of the CNTF-induced response [20].
• Retinoic acid downregulates the expression of ciliary neurotrophic factor in rat Schwann cells [21].
• In vivo, the neuroprotective activity of CNTF in constant-light conditions was attenuated by 10 microg/eye LY294002 (Dunnet's test, p < 0.05) [22].
• Implantation of C6 lines expressing a nonsecreted form of CNTF, or the parental C6 line itself, did not result in wasting effects [10].

Physical interactions of Cntf

• Additionally, IL-6 binding was also competed by CNTF, although not entirely [23].
• Previous studies showed that CNTF regulates fibrinogen gene expression in rat hepatocytes by competitive binding to the IL-6 receptor [24].
• To investigate the role of ciliary neurotrophic factor in the developing and mature brain by defining putative target cells the expression of the ligand-binding alpha-subunit of the ciliary neurotrophic factor receptor was studied in neonatal and adult rat brains using a digoxygenin-labelled probe for in situ hybridization [25].

Co-localisations of Cntf

• Double labeling demonstrated that, in both control and experimental tissue, ciliary neurotrophic factor mRNA was colocalized with glial fibrillary acidic protein immunoreactivity in astroglia, but it was not colocalized with markers for oligodendrocytes or microglia [26].

Regulatory relationships of Cntf

• IL-6 up-regulates CNTF mRNA expression and enhances neurite regeneration [27].
• However, CNTF enhanced BDNF-mediated promotion of cell survival of cholinergic neurons when added concomitantly [28].
• Hepatocyte growth factor promotes motor neuron survival and synergizes with ciliary neurotrophic factor [29].
• This distribution of CNTF-expressing cells corresponded very closely to that of cells expressing high levels of glial fibrillary acidic protein mRNA at the wound site [30].
• Interleukin-6 and ciliary neurotrophic factor trigger janus kinase activation and early gene response in rat hepatocytes [24].

Other interactions of Cntf

• IL-6 (10 ng/ml) also potentiated IL-1beta-mediated NO synthesis and inhibition of insulin release, whereas beta-nerve growth factor (NGF) (5 or 50 ng/ml) had no effect. mRNA for CNTF was expressed in rat islets and in islet cell lines [2].
• Treatment of dissociate cultures of Embryonic Day (E) 16.5 NG with LIF or CNTF (10 ng/ml) resulted in a four- to fivefold increase in neuronal survival; the number of neurons supported by either factor represented approximately 50% of the total NG population [17].
• Expression of CNTF/LIF-receptor components and activation of STAT3 signaling in axotomized facial motoneurons: evidence for a sequential postlesional function of the cytokines [31].
• Our novel findings of increased cardiac CNTF and cardiopulmonary MCP-1 mRNA indicate a role for these factors in the pathogenesis of HF [32].
• Expression of CNTF and GFAP mRNAs followed a time course similar to that of bFGF [33].

Analytical, diagnostic and therapeutic context of Cntf

• In situ hybridizations showed that the elevation of bFGF and CNTF was localized to the vicinity of the lesion [18].
• Using a reverse transcriptase-polymerase chain reaction assay with rat sympathetic neuron cultures, we find that CT-1 induces and suppresses the expression of the same set of neuropeptide and neurotransmitter synthetic enzyme mRNAs as do LIF and CNTF [34].
• In sham-operated as in normal animals, CNTF protein was not detectable by immunocytochemistry [35].
• The expression of CNTF and CNTFR alpha was monitored by reverse transcription-PCR, in situ hybridization, immunoblotting, immunohistochemistry, and electron microscopy [36].
• In situ hybridization experiments revealed that cells expressing CNTF mRNA were concentrated at the margin of the wound, and also present within the gelfoam which filled the lesion cavity [30].

References