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Concept: Ciliary neurotrophic factor

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A high circulating concentration of interleukin 6 is associated with increased risk of coronary heart disease. Blockade of the interleukin-6 receptor (IL6R) with a monoclonal antibody (tocilizumab) licensed for treatment of rheumatoid arthritis reduces systemic and articular inflammation. However, whether IL6R blockade also reduces risk of coronary heart disease is unknown.

Concepts: Immune system, Rheumatoid arthritis, Osteoclast, Interleukin, Interleukin 6, Tocilizumab, Interleukin-6 receptor, Ciliary neurotrophic factor

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To overcome the deficiency of rapid elimination from blood, the truncated human recombinant ciliary neurotrophic factor was formulated by site-specific attachment of different-sized PEG-maleimide or by cross-linking with human transferrin through a hetero-bi-functional PEG linker (NHS-PEG5k-MAL). The PEGylated CNTF was purified by a two-step chromatography procedure and the transferrin coupling CNTF conjugate was separated through an elegant protocol. The conjugation site on CNTF was identified by peptide mapping analysis and validated that the linkage of the conjugates was specifically happened to Cys17 residue. Although both PEGylated and transferrin coupling CNTF demonstrated decreased cell based residual activity, markedly enhanced pharmacokinetic behaviors in normal male Sprague-Dawley rats were observed, especially for the PEG40k-CNTF with approximately 58-times improvement compared with the unmodified counterpart. The evaluation of the in vivo potency of body weight-losing was performed with normal male C57BL6 mice and the results revealed that both PEGylation and transferrin coupling could achieve improved therapeutic benefits relative to that of CNTF. Besides, PEG20k/40k-CNTF demonstrated more effective than transferrin coupling CNTF (Tf-PEG5k-CNTF) despite that the later showed preferable pharmacokinetic profile and cell based residual activity compared with PEG20k-CNTF. Weekly subcutaneous administration of PEG40k-CNTF with 0.5mg/kg and 1.0mg/kg dose resulted in approximately 35% and 50% decrease in food intake during one interval period of injection, indicating that PEG40k-CNTF is the most potential anti-obese agent for therapeutics.

Concepts: Protein, Pharmacology, Human, Neurotrophins, Numerical analysis, Polyethylene glycol, PEGylation, Ciliary neurotrophic factor

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Ciliary neurotrophic factor (CNTF) is involved in the activation of astrocytes. A previous study showed that CNTF-treated astrocyte-conditioned medium (CNTF-ACM) contributed to the increase of the calcium current and the elevation of corresponding ion channels in cortical neurons. On this basis, it is reasonable to assume that CNTF-ACM may increase the intracellular free calcium concentration ([Ca(2+)]i) in neurons. In the present study, the effects of CNTF-ACM on [Ca(2+)]i in rat cortical neurons were determined, and on this basis, the aim was to investigate the potential active ingredients in ACM that are responsible for this biological process. As expected, the data indicated that CNTF-ACM resulted in a clear elevation of [Ca(2+)]i in neurons. Additionally, the fibroblast growth factor-2 (FGF-2) contained in the CNTF-ACM was found to participate in the upregulation of [Ca(2+)]i. Taken together, CNTF induces the production of active factors (at least including FGF-2) released from astrocytes, which finally potentiate the increase of [Ca(2+)]i in cortical neurons.

Concepts: Calcium, Cerebral cortex, Neurotrophins, Neurochemistry, Ciliary neurotrophic factor

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Mutations in the cytokine receptor-like factor 1 (CRLF1) gene are responsible for Crisponi/Cold-induced Sweat Syndrome, an extremely rare autosomal-recessive multisystem disorder. The protein encoded is a soluble cytokine receptor, involved in the ciliary neurotrophic factor receptor (CNTFR) pathway. The ciliary neurotrophic factor (CNTF) promotes corneal wound healing and patients with Crisponi/CISS1 syndrome suffer from recurrent keratitis. The aim of the study was to report and discuss the corneal alterations in Crisponi/CISS1 rare disease.

Concepts: DNA, Protein, Wound healing, Receptor, Microscopy, Neurotrophins, Ciliary neurotrophic factor, Ciliary neurotrophic factor receptor

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Ciliary neurotrophic factor (CNTF) exerts powerful anorectic effects and has been suggested to regulate long-term energy balance by inducing adult neurogenesis in the arcuate nucleus of the hypothalamus.

Concepts: Hypothalamus, Neurotrophins, Arcuate nucleus, Ciliary neurotrophic factor, Axokine

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Interleukin-6 (IL-6) cytokine signaling is key in Rheumatoid Arthritis (RA) pathophysiology. Blocking IL-6 receptor (IL6R) has proven to be a highly effective treatment to prevent joint damage. This study was performed to investigate the association between the genetic variation at IL6R gene and the severity of joint damage in RA.

Concepts: Rheumatoid arthritis, Interleukin 6, Tocilizumab, Interleukin-6 receptor, Ciliary neurotrophic factor

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To evaluate the safety and tolerability of intraocular delivery of ciliary neurotrophic factor (CNTF) using an encapsulated cell implant for the treatment of macular telangiectasia type 2.

Concepts: Neurotrophin, Brain-derived neurotrophic factor, Neurotrophins, Ciliary neurotrophic factor

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Abstract Our lab has previously shown that Interleukin (IL)-6- dependent production of autoantibodies against aquaporin 4 in plasmablasts may play a central role in the pathogenesis of neuromyelitis optica (NMO). In this study, we explored the efficacy of tocilizumab, a humanized antibody against IL-6 receptor, in intractable cases of NMO. Eight NMO patients who were unresponsive to current treatments received monthly injections of tocilizumab for at least one year. Tocilizumab significantly reduced the annual relapse rate, neurogenic pain, and fatigue in NMO patients. These results indicate that IL-6 signaling plays a crucial role in the pathogenesis of NMO and highlight the value of IL-6 receptor inhibition for the treatment of NMO.

Concepts: Immune system, Osteoclast, Multiple sclerosis, Interleukin, Interleukin 6, Tocilizumab, Interleukin-6 receptor, Ciliary neurotrophic factor

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Interleukin (IL)-6-deficient, but not IL-6 receptor (IL-6R)‑deficient mice present with a delayed skin wound healing phenotype. Since IL-6 solely signals via the IL-6R and glycoprotein 130 (gp130), Il-6r-deficient mice are expected to exhibit a similar phenotype as Il-6-deficient mice. However, p28 (IL-30) and ciliary neurotrophic factor (CNTF) have been identified as additional low‑affinity ligands of the IL-6R/gp130/LIFR complex. IL-6 plays an inflammatory and regenerative role in inflammatory bowel disease (IBD). In the present study, we compared Il-6r-deficient mice with mice treated with neutralizing IL-6 monoclonal antibody (mAb) in a model of dextran sodium sulfate (DSS)-induced colitis. Our results, in agreement with those of previous reports, demonstrated that IL-6 mAbs slightly attenuated DSS-induced colitis during the regeneration phase. Il-6r-deficient mice and mice with tissue-specific deletion of the Il-6r in the myeloid cell lineage (LysMCre) with acute and chronic DSS-induced colitis were, however, indistinguishable from wild-type mice. Our data suggest that IL-6 and IL-6R have an additional role in colitis, apart from the IL-6/IL-6R classic and trans-signaling.

Concepts: Immune system, Inflammation, Monoclonal antibodies, Ulcerative colitis, Inflammatory bowel disease, Interleukin 6, Interleukin-6 receptor, Ciliary neurotrophic factor

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Ciliary neurotrophic factor (CNTF) is a neurotrophic factor with therapeutic potential for neurodegenerative diseases. Moreover, therapeutic application of CNTF reduced body weight in mice and humans. CNTF binds to high or low affinity receptor complexes consisting of CNTFR/gp130/LIFR or IL-6R/gp130/LIFR, respectively. Clinical studies of the CNTF derivative Axokine revealed intolerance at higher concentrations, which may rely on the low-affinity binding of CNTF to the IL-6R. Here, we aimed to generate a CNTFR-selective CNTF variant (CV). CV-1 contained the single amino acid exchange R28E. R28 is in close proximity to the CNTFR binding site. Using molecular modelling we hypothesised that R28 might contribute to IL-6R/CNTFR plasticity of CNTF. CV-2 to CV-5 were generated by transferring parts of the CNTFR binding site from Cardiotrophin-like cytokine (CLC) to CNTF. CLC selectively signals via the CNTFR/gp130/LIFR complex, albeit with a much lower affinity compared to CNTF. As shown by immunoprecipitation, all CNTF variants retained the ability to bind to CNTFR. CV-1, CV-2 and CV-5, however, lost the ability to bind to IL-6R. Although all variants induced cytokine-dependent cellular proliferation and STAT3 phosphorylation via CNTFR/gp130/LIFR, only CV-3 induced STAT3 phosphorylation via IL-6R/gp130/LIFR. Quantification of CNTF-dependent proliferation of CNTFR-gp130-LIFR expressing cells indicated that only CV-1 was as biologically active as CNTF. Thus, the CNTFR-selective CV-1 will allow discriminating between CNTFR- and IL-6R-mediated effects in vivo.

Concepts: Proteins, Protein, Amino acid, Amine, Neurotrophins, Ciliary neurotrophic factor, Ciliary neurotrophic factor receptor, Axokine