Microchemotaxis chambers were used to investigate whether one aspect of ciliary neurotrophic factor CNTF’s role as a lesion factor might be to promote the initial early recruitment of macrophages, which express the signal transducing receptor components, gp130 and LIFRβ. CNTFRα alone, or in combination with CNTF, elicited concentration-dependent macrophage chemotaxis that was inhibited by a neutralizing gp 130 antibody. IL-6, but not LIF, similarly promoted gp 130-dependent macrophage chemotaxis. Stimulation of macrophages with either CNTFRα in combination with CNTF or IL-6 alone resulted in tyrosine phosphorylation of a ~130kD protein, presumed to be gp130. Macrophage chemotaxis induced by the combination of CNTFRα and CNTF was inhibited in a dose-dependent fashion by wortmannin, LY294002 or PD98059, suggesting the involvement of the phosphoinositide-3 kinase and mitogen-activated protein kinase signaling proteins. As CNTFRα and CNTF are present, or have immediate access to nerves after injury, these data point to the possibility that this soluble receptor alone or in combination with its ligand may promote the initial early recruitment of macrophages in vivo.