Disease relevance of CNTF

• In contrast, inactivation of the CNTF gene leads only to a slight muscle weakness, mainly during adulthood, suggesting that CNTFR binds to a second ligand that is important for development [1].
• To elucidate the molecular mechanisms mediating the transcriptional activation by CNTF, intracellular signaling to the CyRE has been studied in a neuroblastoma cell line [2].
• Ciliary neurotrophic factor (CNTF), a cytokine closely related to leptin, reduces food intake and reverses obesity, but its role in restoring the starvation-induced changes of hormones or hypothalamic neuropeptides remains largely unknown [3].
• Ciliary neurotrophic factor (CNTF) has recently been found to be important for the survival of motor neurons and has shown activity in animal models of amyotrophic lateral sclerosis (ALS) [4].
• The neurotrophins are currently under investigation as therapeutic agents for the treatment of neurodegenerative disorders and nerve injury either individually or in combination with other trophic factors such as ciliary neurotrophic factor (CNTF) or fibroblast growth factor (FGF) [5].

Psychiatry related information on CNTF

• Solution structure of the C-terminal domain of the ciliary neurotrophic factor (CNTF) receptor and ligand free associations among components of the CNTF receptor complex [6].
• Ciliary neurotrophic factor (CNTF) has been shown to prevent behavioral deficits and striatal degeneration in neurotoxic models of Huntington's disease (HD), but its effect in a genetic model has not been evaluated [7].
• Disturbances in the biology of NTFs and CNTF have recently been implicated in the pathogenesis of certain common neurodegenerative disorders, such as Parkinson's disease, motor neurone diseases, and Alzheimer's disease [8].
• These results support the hypothesis that CNTF infusion into the striatum of HD patients not only could block the degeneration of neurons but also alleviated motor and cognitive symptoms associated with persistent neuronal dysfunction [9].
• Body weight (BW), body composition, leptin concentration, attitude toward eating (measured with the Three-Factor Eating Questionnaire), physical activity, and the polymorphisms of the PPARgamma2, GRL, and CNTF genes were measured [10].

High impact information on CNTF

• Mice lacking the CNTF receptor, unlike mice lacking CNTF, exhibit profound motor neuron deficits at birth [11].
• The distribution of the three genotypes is similar in healthy and neurological disease subjects, indicating that human CNTF deficiency is not causally related to neurological diseases [12].
• Analysis of tissue samples and transfection of CNTF minigenes into cultured cells demonstrates that the mutated allele expresses only the mutated mRNA species [12].
• Sensory neurons, however, became refractory to bcl-2 after exposure to CNTF [13].
• Sensory neurons that depend for survival on one or more members of the nerve growth factor family of neurotrophic factors (nerve growth factor, brain-derived neurotrophic factor, and neurotrophin-3) were rescued by bcl-2, whereas ciliary neurotrophic factor (CNTF)-dependent ciliary neurons were not [13].

Chemical compound and disease context of CNTF

• Thus, retinoic acid and TPA regulate CNTF receptors on neuroblastoma cells differently, and the results demonstrate the importance of transcriptional control of CNTF receptors and also implicate translational and post-translational mechanisms in the regulation of cytokine receptors and responses on neurons [14].
• Treatment with hydrogen peroxide (H(2)O(2)) as a generator of ROS inhibited CNTF-mediated Jak/STAT signaling in all cultured nerve cells tested, including chick ciliary ganglion neurons, chick neural retina, HMN-1 motor neuron hybrid cells, and SH-SY5Y and BE(2)-C human neuroblastoma cells [15].
• Coadministration of the mitotic blocker cytosine-beta-d-arabinofuranoside (Ara-C) eliminates the proliferation of neural cells and abrogates the long-term, but not the short-term, effect of CNTF on body weight [16].
• We found that divalent cadmium (CdCl2) inhibited ciliary neurotrophic factor (CNTF)-mediated Jak1 and Jak2 tyrosine kinase signaling in human BE(2)-C neuroblastoma cells [17].
• Ciliary neurotrophic factor (CNTF) induces weight loss and improves glucose tolerance in humans and rodents [18].

Biological context of CNTF

• Unlike other cytokine receptors studied to date, the receptors for the CNTF cytokine family utilize all known members of the Jak-Tyk family, but induce distinct patterns of Jak-Tyk phosphorylation in different cell lines [19].
• Thus, we have identified a protein complex binding to a novel DNA sequence that is necessary for full CNTF induction of VIP gene transcription [20].
• Mutations in an 8-bp sequence (TTACTGGA) eliminated binding of this protein complex and markedly reduced transcriptional activation of the CyRE by CNTF [20].
• Similarly, we also characterized two additional antibodies B-P8 and B-P4, which inhibited the TF1 cell proliferation observed in the presence of CNTF and IL-11, respectively [21].
• Besides identifying a specific LIFR binding epitope on CNTF, our results suggest that receptor recognition sites of cytokines are organized as modules that are exchangeable even between cytokines with limited sequence homology [22].

Anatomical context of CNTF

• The physiological and pathophysiological functions of neurotrophins and CNTF are discussed in the context of their potential use for the treatment of traumatic and degenerative diseases of the peripheral and central nervous systems [23].
• Such dimers are likely to be relevant to the storage of CNTF in the peripheral nerve given the high concentrations present in this tissue [24].
• Ciliary neurotrophic factor (CNTF), which acts parallel to leptin in the hypothalamus, is not previously recognized to have cardiac activity [25].
• Retrograde transport of radiolabeled CNTF has only been observed in sensory neurons of the sciatic nerve [26].
• GPAR alpha mRNA expression is largely restricted to the nervous system and was detected in all neurons that have been shown to respond to GPA or CNTF by increased survival or differentiation, i.e. ciliary, sympathetic, sensory dorsal root, motoneurons, retinal ganglion cells and amacrine cells [27].

Associations of CNTF with chemical compounds

• Both CNTF and LIF trigger the association of initially separate receptor components, which in turn results in tyrosine phosphorylation of receptor subunits [28].
• Serine phosphorylation and maximal activation of STAT3 during CNTF signaling is mediated by the rapamycin target mTOR [29].
• Cells treated for 24 h with retinoic acid (10 microM) showed a threefold increase in 125I-CNTF binding sites and were up to five times more sensitive to CNTF than untreated cells in stimulating the tyrosine phosphorylation of the transcription factor STAT3 [14].
• Further studies are, however, needed to investigate the intracellular signaling pathways mediating the long-term effects of CNTF expression on dopamine signaling, glial cell activation and how these changes may affect HD pathology [7].
• The retinoic acid-induced increase in 125I-CNTF binding could be prevented by administration of either cycloheximide or actinomycin D, whereas neither agent altered the TPA-induced decrease in 125I-CNTF binding [14].

Physical interactions of CNTF

• Receptor recognition sites of cytokines are organized as exchangeable modules. Transfer of the leukemia inhibitory factor receptor-binding site from ciliary neurotrophic factor to interleukin-6 [22].
• Here we show that the CBD of human gp130 can also bind in vitro to sCNTFR in the absence of CNTF [6].
• Apolipoprotein E binds to and potentiates the biological activity of ciliary neurotrophic factor [30].
• Recent data have indicated that CNTFR alpha must bind CNTF, then interact with two other "beta" receptor components to initiate signal transduction [31].
• In contrast, ciliary neurotrophic factor employs a receptor system that shares components with the receptor complexes for a subclass of distantly related hematopoietic cytokines [32].

Enzymatic interactions of CNTF

• A STAT3 peptide was efficiently phosphorylated on Ser727 in a CNTF-dependent manner by mTOR, but not by a kinase-inactive mTOR mutant or by p70 S6 kinase [29].

Regulatory relationships of CNTF

• CdCl2 concentrations as low as 0.1 microM and for times as brief as 2 h significantly reduced CNTF-induced tyrosine phosphorylation of both STAT1 and STAT3, the principle substrates of Jak kinases in neurons [17].
• Treatment of cells with CNTF induced a rapid tyrosine phosphorylation of STAT3 followed by a time-dependent decay of this signal [33].
• However, in the presence of a 10-fold excess of sCNTFR alpha, 300 ng/ml of CNTF suppressed IL-1 alpha-induced IL-8 by 44% [34].
• Moreover, cotreatment with bFGF reduced the ability of CNTF to enhance choline acetyltransferase [35].
• Integration of Jak-Stat and AP-1 signaling pathways at the vasoactive intestinal peptide cytokine response element regulates ciliary neurotrophic factor-dependent transcription [2].

Other interactions of CNTF

• However, it is unlikely that they play a role in engaging the three distinct receptor subunits that comprise the CNTF receptor, given the low concentration of extracellular CNTF and its high potency [24].
• The D1 structural motif, located at the beginning of the D-helix of human CNTF, contains two amino acid residues, F152 and K155, which are conserved among all cytokines that signal through LIFR [36].
• CDF/LIF is a polyfunctional cytokine that shares a remarkable overlap with ciliary neurotrophic factor in its actions on neurons, and with interleukin-6 in its actions on other tissues [37].
• Several families of growth promoting substances have been identified within the central nervous system (CNS) including the superfamily of nerve growth factor related neurotrophin factors, glial derived neurotrophic factor (GDNF) and ciliary neurotrophic factor (CNTF) [26].
• However, IL-6 and CNTF do not exhibit this cross-talk ability [38].

Analytical, diagnostic and therapeutic context of CNTF

• Treatment of isolated atria or cultured atrial myocytes with recombinant human or avian CNTF resulted in the tyrosine phosphorylation and nuclear translocation of the signal transducer and activator of transcription STAT3 [39].
• Response to CNTF correlated with expression of membrane CNTF receptor alpha-chain (CNTFR alpha), as shown by PCR analysis and immunostaining with anti-CNTFR alpha antibodies [40].
• In the control group LIF, CNTF and IL-11 were measurable in 8.3%, 33.3% and 8.3% respectively [41].
• Retinal progenitors, cultured alone or as a co-culture in the rotating bioreactor, formed 3D structures with some degree of differentiation, accompanied by the upregulation of bFGF, CNTF, and TGFalpha [42].
• Northern blot analysis revealed that 3 of the 11 cell lines expressed c-fos mRNA after CNTF stimulation [43].

References