title: The cytokines cardiotrophin-like cytokine/cytokine-like factor-1 (CLC/CLF) and ciliary neurotrophic factor (CNTF) differ in their receptor specificities.
abstract: Ciliary neurotrophic factor (CNTF) and cardiotrophin-like cytokine (CLC) are two cytokines with neurotrophic and immunomodulatory activities. CNTF is a cytoplasmic factor believed to be released upon cellular damage, while CLC requires interaction with a soluble cytokine receptor, cytokine-like factor 1 (CLF), to be efficiently secreted. Both cytokines activate a receptor complex comprising the cytokine binding CNTF receptor α (CNTFRα) and two signaling chains namely, leukemia inhibitory factor receptor β (LIFRβ) and gp130. Human CNTF can recruit and activate an alternative receptor in which CNTFRα is substituted by IL-6Rα. As both CNTF and CLC have immune-regulatory activities in mice, we compared their ability to recruit mouse receptors comprising both gp130 and LIFRβ signaling chains and either IL-6Rα or IL-11Rα which, unlike CNTFRα, are expressed by immune cells. Our results indicate that 1) mouse CNTF, like its human homologue, can activate cells expressing gp130/LIFRβ with either CNTFRα or IL-6Rα and, 2) CLC/CLF is more restricted in its specificity in that it activates only the tripartite CNTFR. Several gp130 signaling cytokines influence T helper cell differentiation. We therefore investigated the effect of CNTF on CD4 T cell cytokine production. We observed that CNTF increased the number of IFN-γ producing CD4 T cells. As IFN-γ is considered a mediator of the therapeutic effect of IFN-β in multiple sclerosis, induction of IFN-γ by CNTF may contribute to the beneficial immunomodulatory effect of CNTF in mouse multiple sclerosis models. Together, our results indicate that CNTF activates the same tripartite receptors in mouse and human cells and further validate rodent models for pre-clinical investigation of CNTF and CNTF derivatives. Furthermore, CNTF and CLC/CLF differ in their receptor specificities. The receptor α chain involved in the immunomodulatory effects of CLC/CLF remains to be identified.
authors.affiliation: Département de Pharmacologie, Université de Montréal, Montreal, QC, Canada.
authors.forename: Aurélie Jeanne
authors.initials: AJ
authors.lastname: Tormo
authors.forename: Marie-Claude
authors.initials: MC
authors.lastname: Letellier
authors.forename: Rami
authors.initials: R
authors.lastname: Lissilaa
authors.forename: Laurie-Anne
authors.initials: LA
authors.lastname: Batraville
authors.forename: Mukut
authors.initials: M
authors.lastname: Sharma
authors.forename: Walter
authors.initials: W
authors.lastname: Ferlin
authors.forename: Greg
authors.initials: G
authors.lastname: Elson
authors.forename: Sandrine
authors.initials: S
authors.lastname: Crabé
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Gauchat
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism*; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D020934:Ciliary Neurotrophic Factor / Q000378:metabolism*; D053739:Ciliary Neurotrophic Factor Receptor alpha Subunit / Q000378:metabolism*; D050822:Cytokine Receptor gp130 / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism*; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D053703:Interleukin-11 Receptor alpha Subunit / Q000378:metabolism; D053680:Leukemia Inhibitory Factor Receptor alpha Subunit / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018121:Receptors, Cytokine / Q000378:metabolism*; D019947:Receptors, Interleukin-6 / Q000378:metabolism; D015398:Signal Transduction; D006377:T-Lymphocytes, Helper-Inducer / Q000378:metabolism
chemical_list: D020934:Ciliary Neurotrophic Factor; D053739:Ciliary Neurotrophic Factor Receptor alpha Subunit; D016207:Cytokines; C494200:Il6st protein, mouse; D053703:Interleukin-11 Receptor alpha Subunit; D053680:Leukemia Inhibitory Factor Receptor alpha Subunit; C507841:Lifr protein, mouse; D018121:Receptors, Cytokine; D019947:Receptors, Interleukin-6; C121169:cardiotrophin-like cytokine; C113554:cytokine-like factor-1; C113250:interleukin-6 receptor alpha; D050822:Cytokine Receptor gp130; D007371:Interferon-gamma