The cytokines cardiotrophin-like cytokine/cytokine-like factor-1 (CLC/CLF) and ciliary neurotrophic factor (CNTF) differ in their receptor specificities

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 alpha (CNTFR alpha) and two signaling chains namely, leukemia inhibitory factor receptor beta (LIFR beta) and gp130. Human CNTF can recruit and activate an alternative receptor in which CNTFR alpha is substituted by IL-6R alpha. As both CNTF and CLC have immune-regulatory activities in mice, we compared their ability to recruit mouse receptors comprising both gp130 and LIFR beta signaling chains and either IL-6R alpha or IL-11R alpha which, unlike CNTFR alpha, are expressed by immune cells. Our results indicate that 1) mouse CNTF, like its human homologue, can activate cells expressing gp130/LIFR beta with either CNTFR alpha or IL-6R alpha 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 CD4T cell cytokine production. We observed that CNTF increased the number of IFN-gamma producing CD4T cells. As IFN-gamma is considered a mediator of the therapeutic effect of IFN-beta in multiple sclerosis, induction of IFN-gamma 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 alpha chain involved in the immunomodulatory effects of CLC/CLF remains to be identified. Crown Copyright (C) 2012 Published by Elsevier Ltd. All rights reserved.