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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2013/01/20 15:24:26」(JST)

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Ciliary neurotrophic factor is a protein that in humans is encoded by the CNTF gene.^[1]^[2]^[3]

The protein encoded by this gene is a polypeptide hormone and nerve growth factor whose actions have mainly been studied in the nervous system where it promotes neurotransmitter synthesis and neurite outgrowth in certain neuronal populations including astrocytes. The protein is a potent survival factor for neurons and oligodendrocytes and may be relevant in reducing tissue destruction during inflammatory attacks. A mutation in this gene, which results in aberrant splicing, leads to ciliary neurotrophic factor deficiency, but this phenotype is not causally related to neurologic disease. In addition to the predominant monocistronic transcript originating from this locus, the gene is also co-transcribed with the upstream ZFP91 gene. Co-transcription from the two loci results in a transcript that contains a complete coding region for the zinc finger protein but lacks a complete coding region for ciliary neurotrophic factor.^[3] CNTF has also been shown to be expressed by cells on the bone surface, and to reduce the activity of bone forming cells, osteoblasts.^[4]

Therapeutic applications

Satiety effects

In 2001, it was reported that in a human study examining the usefulness of CNTF for treatment of motor neuron disease, CNTF produced an unexpected and substantial weight loss in the study subjects. Further investigation revealed that CNTF could reduce food intake without causing hunger or stress, making it a candidate for weight control in leptin resistant subjects, as CNTF is believed to operate like leptin, but by a non-leptin pathway.^[5]

Axokine

Axokine is a modified version of human Ciliary neurotrophic factor with a 15 amino acid truncation of the C terminus and two amino acid substitutions, which is three to five times more potent than CNTF in in vitro and in vivo assays and has improved stability properties.^[6] Like CNTF it is a neurotrophic factor, and may stimulate nerve cells to survive. It was tested in the 1990s as a treatment for amyotrophic lateral sclerosis. It did not improve muscle control as much as expected, but trial participants did report a loss of appetite.

Phase III clinical trials for the drug against obesity were conducted in 2003 by Axokine's maker, Regeneron, demonstrating a small positive effect in some patients, but the drug was not commercialized. A major problem with the treatment was that in nearly 70% of the subjects tested, antibodies against Axokine were produced after approximately three months of treatment.^[7] In the minority of subjects who did not develop the antibodies, weight loss averaged 12.5 pounds in one year, versus 4.5 pounds for placebo-treated subjects. In order to obtain this benefit, subjects needed to receive daily subcutaneous injections of one microgram Axokine per kilogram body weight.

Xencor patent application raises the disturbing idea that subjects producing antibodies against CNTF analogues may eventually suffer severe side effects, as these antibodies could potentially interfere with the neuroprotective functions of endogenous CNTF.^[8] The application claims methods of designing CNTF analogues with lower immunogenicity than Axokine based on analysis of affinity of each modified epitope for each of 52 class II MHC alleles, and provides specific examples of such modifications. No such analogues are currently listed in Xencor's product pipeline.^[9]

NT-501

NT-501 is a product being developed by Neurotech that consists of encapsulated human cells genetically modified to secrete ciliary neurotrophic factor (CNTF). In a clinical trial, NT-501 demonstrated a statistically significant reduction of photoreceptor degradation in patients with retinitis pigmentosa.^[10]^[11]

Interactions

Ciliary neurotrophic factor has been shown to interact with Interleukin-6 receptor.^[12]^[13]

References

^ Lam A, Fuller F, Miller J, Kloss J, Manthorpe M, Varon S, Cordell B (Sep 1991). "Sequence and structural organization of the human gene encoding ciliary neurotrophic factor". Gene 102 (2): 271–6. doi:10.1016/0378-1119(91)90089-T. PMID 1840538.
^ Bazan JF (Sep 1991). "Neuropoietic cytokines in the hematopoietic fold". Neuron 7 (2): 197–208. doi:10.1016/0896-6273(91)90258-2. PMID 1714745.
^ ^a ^b "Entrez Gene: CNTF ciliary neurotrophic factor". http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=1270.
^ McGregor NE, Poulton IJ, Walker EC, Pompolo S, Quinn JM, Martin TJ, Sims NA (Mar 2010). "Ciliary neurotrophic factor inhibits bone formation and plays a sex-specific role in bone growth and remodeling". Calcified Tissue International 86 (3): 261–70. doi:10.1007/s00223-010-9337-4. PMID 20157807.
^ Lambert PD, Anderson KD, Sleeman MW, Wong V, Tan J, Hijarunguru A, Corcoran TL, Murray JD, Thabet KE, Yancopoulos GD, Wiegand SJ (2001). "Ciliary neurotrophic factor activates leptin-like pathways and reduces body fat, without cachexia or rebound weight gain, even in leptin-resistant obesity". Proc. Natl. Acad. Sci. U.S.A. 98 (8): 4652–7. doi:10.1073/pnas.061034298. PMC 31889. PMID 11259650. //www.ncbi.nlm.nih.gov/pmc/articles/PMC31889/.
^ Peterson WM, Wang Q, Tzekova R, Wiegand SJ (June 2000). "Ciliary neurotrophic factor and stress stimuli activate the Jak-STAT pathway in retinal neurons and glia". J. Neurosci. 20 (11): 4081–90. PMID 10818143.
^ "Axokine from Regeneron (REGN): Unexpected Antibodies and Modest Efficacy in Phase III Study". Press Release. Regeneron Pharmaceuticals. 2003-03-31. http://www.pharmagon.com/Library/InfoManage/Zoom.asp?InfoID=1813&RedirectPath=Add&FolderID=1561&InfoGroup=Main&InfoType=Article. Retrieved 2011-08-20.
^ US application 2005064555, Marshall S, Barbosa M, "Ciliary neurotrophic factor variants", published 2005-03-24
^ "Product Pipeline". Xencor. http://www.xencor.com/products/pipeline/. Retrieved 2011-08-20.
^ Talcott KE, Ratnam K, Sundquist SM, Lucero AS, Lujan BJ, Tao W, Porco TC, Roorda A, Duncan JL (April 2011). "Longitudinal study of cone photoreceptors during retinal degeneration and in response to ciliary neurotrophic factor treatment". Invest. Ophthalmol. Vis. Sci. 52 (5): 2219–26. doi:10.1167/iovs.10-6479. PMID 21087953.
^ "Neurotech’s NT-501 Implant Demonstrates Statistically Significant Photoreceptor Preservation in Patients with Retinal Degenerative Disease |". Business Wire. 2011-04-11. http://www.businesswire.com/news/home/20110414005343/en/Neurotechâ€™s-NT-501-Implant-Demonstrates-Statistically-Significant-Photoreceptor. Retrieved 2011-08-20.
^ Schuster B, Kovaleva M, Sun Y, Regenhard P, Matthews V, Grötzinger J, Rose-John S, Kallen KJ (March 2003). "Signaling of human ciliary neurotrophic factor (CNTF) revisited. The interleukin-6 receptor can serve as an alpha-receptor for CTNF". J. Biol. Chem. 278 (11): 9528–35. doi:10.1074/jbc.M210044200. PMID 12643274.
^ Schooltink H, Stoyan T, Roeb E, Heinrich PC, Rose-John S (December 1992). "Ciliary neurotrophic factor induces acute-phase protein expression in hepatocytes". FEBS Lett. 314 (3): 280–4. doi:10.1016/0014-5793(92)81489-9. PMID 1281789.

External links

Ciliary+neurotrophic+factor at the US National Library of Medicine Medical Subject Headings (MeSH)

UpToDate Contents

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1. ハンチントン病：管理 huntington disease management
2. 成人における発熱の病態生理および治療 pathophysiology and treatment of fever in adults
3. 筋萎縮性側索硬化症の疫学および病因 epidemiology and pathogenesis of amyotrophic lateral sclerosis
4. 筋萎縮性側索硬化症の病態修飾療法 disease modifying treatment of amyotrophic lateral sclerosis
5. 幼児および小児における発熱の病態生理およびマネージメント pathophysiology and management of fever in infants and children

English Journal

Interleukin-6 is an efficacious marker of axonal transport disruption during experimental glaucoma and stimulates neuritogenesis in cultured retinal ganglion cells.

Chidlow G, Wood JP, Ebneter A, Casson RJ.SourceOphthalmic Research Laboratories, South Australian Institute of Ophthalmology, Hanson Institute Centre for Neurological Diseases, Frome Rd, Adelaide, SA 5000, Australia; Department of Ophthalmology and Visual Sciences, University of Adelaide, Frome Rd, Adelaide, SA 5000, Australia. Electronic address: glyn.chidlow@health.sa.gov.au.
Neurobiology of disease.Neurobiol Dis.2012 Dec;48(3):568-81. doi: 10.1016/j.nbd.2012.07.026. Epub 2012 Aug 4.
It is increasingly recognised that chronically activated glia contribute to the pathology of various neurodegenerative diseases, including glaucoma. One means by which this can occur is through the release of neurotoxic, proinflammatory factors. In the current study, we therefore investigated the sp
PMID 22884876

Serotonin 1A receptor agonist increases species- and region-selective adult CNS proliferation, but not through CNTF.

Arnold SA, Hagg T.SourceKentucky Spinal Cord Injury Research Center, University of Louisville, KY 40292, USA; Department of Neurological Surgery, University of Louisville, KY 40292, USA.
Neuropharmacology.Neuropharmacology.2012 Dec;63(7):1238-47. Epub 2012 Aug 5.
Endogenous ciliary neurotrophic factor (CNTF)(1) regulates neurogenesis of the adult brain in the hippocampal subgranular zone (SGZ)(2) and the subventricular zone (SVZ)(3). We have previously shown that the cAMP-inhibiting D2 dopamine receptor increases neurogenesis by inducing astroglial CNTF expr
PMID 22884499

Japanese Journal

Leukemia inhibitory factor receptor and schizophrenia

Kameno Yosuke,Suzuki Katsuaki,Wakuda Tomoyasu,Takebayashi Kiyokazu,Iwata Keiko,Tsuchiya Kenji J.,Matsuzaki Hideo,Takagai Shu,Iwata Yasuhide,Nakamura Kazuhiko,Mori Norio
Journal of brain science 36, 32-45, 2011-03-30
… Leukemia inhibitory factor-receptor (LIFR) is known to play a major role in neurogenesis promotions and stem cell self-renewal via binding to their ligands, leukemia inhibitory factor (LIF) and ciliary neurotrophic factor (CNTF). … First, we measured the mRNA levels of LIFR, LIF and CNTF in peripheral lymphocytes from drug-naive patients with schizophrenia (n=22) and from age-and gender- matched healthy controls (n=44) using quantitative real-time RT-PCR. …
NAID 110008574013

眼科医にもわかる生理活性物質と眼疾患の基本(15)CNTF

竹内侯雄,中澤満
臨床眼科 65(3), 276-278, 2011-03-00
NAID 40018772177

サイトカインの役割 (糖尿病性細小血管症(第2版)--発症・進展制御の最前線) -- (糖尿病性細小血管症の発症・進展の分子メカニズム)

木原進士
日本臨床 68(-) (988), 65-69, 2010-11-00
NAID 40017392172

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★リンクテーブル★

リンク元	「サイトカイン受容体」「毛様体神経栄養因子」「繊毛様神経栄養因子」「繊毛神経栄養因子」
拡張検索	「CNTF receptor」「CNTF受容体」「CNTFレセプター」

「サイトカイン受容体」

Ciliary neurotrophic factor
	; PDB rendering based on 1cnt.
Available structures
PDB	Ortholog search: PDBe, RCSB
List of PDB id codes
	1CNT
Identifiers
Symbols	CNTF; HCNTF
External IDs	OMIM: 118945 MGI: 88439 HomoloGene: 8288 GeneCards: CNTF Gene
Gene Ontology
Molecular function	• cytokine activity; • ciliary neurotrophic factor receptor binding; • interleukin-6 receptor binding; • growth factor activity;
Cellular component	• extracellular space; • nucleus; • cytosol; • axon; • cell projection cytoplasm; • neuronal cell body; • intracellular membrane-bounded organelle; • CRLF-CLCF1 complex;
Biological process	• signal transduction; • JAK-STAT cascade; • positive regulation of cell proliferation; • positive regulation of phosphatidylinositol 3-kinase cascade; • positive regulation of cell growth; • growth; • positive regulation of tyrosine phosphorylation of Stat3 protein; • positive regulation of MAPK cascade; • negative regulation of neuron apoptotic process; • negative regulation of photoreceptor cell differentiation; • regulation of retinal cell programmed cell death; • positive regulation of hormone secretion; • astrocyte activation; • muscle organ morphogenesis; • neuron development; • positive regulation of axon regeneration; • regulation of resting membrane potential; • membrane hyperpolarization; • ciliary neurotrophic factor-mediated signaling pathway;
	Sources: Amigo / QuickGO
RNA expression pattern
	More reference expression data
Orthologs
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