Neurotrophic Action of Interleukin 3 and Granulocyte-Macrophage Colony-Stimulating Factor on Murine Sympathetic Neurons

Abstract

We investigated neurotrophic effects of interleukin 3 (IL-3) and granulocyte-macrophage colony-stimulating factor (GM-CSF) on cultured sympathetic neurons obtained from mouse superior cervical ganglia. After 1 day of culture with physiological concentrations of mouse recombinant IL-3 and GM-CSF, the numbers of process-bearing neurons were increased. Maximum responses were elicited by 10 U/ml IL-3 and 1 U/ml GM-CSF, which were equivalent to the action of a submaximal dose (5 ng/ml) of nerve growth factor (NGF). The effects of IL-3 and GM-CSF were completely blocked by their corresponding antibodies, but not by anti-NGF, indicting their action is specific and completely independent of NGF. IL-3 and, to a lesser extent, GM-CSF were also able to protect NGF-differentiated neurons from apoptotic cell death caused by NGF withdrawal. The mitogen-activated protein (MAP) kinase signal transduction pathway is known to be involved in action of IL-3 and GM-CSF on hemopoietic cells, and thus we examined the participation of this pathway in the neurotrophic activities of IL-3 and GM-CSF. IL-3 and GM-CSF stimulation of the differentiated neurons was found to result in a rapid elevation of MAP kinase activity, and PD98059, an inhibitor of MAP kinase kinase activity, blocked both the neuritogenic and neuroprotective effects of IL-3 and GM-CSF. Immunocytochemical studies showed that IL-3 and GM-CSF receptors were present on the differentiated neurons. Thus, IL-3 and GM-CSF appear to be able to stimulate sympathetic nerve growth, via specific cytokine receptors on neurons, which lead to activation of the MAP kinase pathway that then mediates the observed neurotrophic effects.

Changes in the density and distribution of sympathetic nerves in spleens from Lewis rats with adjuvant‐induced arthritis suggest that an injury and sprouting response occurs

“…Application of granulation tissue, rich in ED1 ϩ and ED2 ϩ macrophages, enhances regeneration of peripheral nerves after a test crush lesion (Miyauchi et al, 1997), a responses that may involve IL-1, insofar as IL-1 stimulates the local synthesis of nerve growth factor (NGF) by infiltrating macrophages (Heumann, 1987). Many factors produced by lymphoid cells are neurotrophic, including interleukins other than IL-1 (Kashima et al, 1992;Mehler et al, 1993;Awatsuji et al, 1993;Araujo and Cotman, 1993;van Coelln et al, 1995), granulocyte-macrophage colony-stimulating factor (van Coelln et al, 1995;Kannan et al, 2000), transforming growth factor-␤ (TGF␤; Poulsen et al, 1994), stem cell factor (Carnahan et al, 1994), and leukemia inhibitor factor (Murphy et al1993). Recently, IL-12 and IL-3 also have been reported to stimulate sympathetic neurite growth in mouse sympathetic superior cervical ganglion neurons (Kannan et al, 2000;Lin et al, 2000).…”

GM-CSF inhibits glial scar formation and shows long-term protective effect after spinal cord injury

“…GM-CSF can function as a neurotrophic factor [9] and induce proliferation of neural progenitor cells (NPCs) [10] in vitro. Therapeutic effect of GM-CSF is already well known in the peripheral nervous system (PNS) injury by activating macrophages and Schwann cells to remove myelin debris [11][12][13].…”

Neuritogenic Effects of T Cell-Derived IL-3 on Mouse Splenic Sympathetic Neurons In Vivo

“…Treatment of animals with anti-IL-3 Ab blocked the ability of T cell reconstitution to enhance neuritogenesis, supporting its importance in this process. We previously demonstrated that IL-3 exerted a neurotrophic effect on cultured sympathetic neurons by a receptor-mediated process that involved the MAPK pathway (10). We also found that IL-3 stimulated neurons in nematode-infected lymphoid tissues in a coculture system (12).…”

“…Primary and secondary lymphoid organs are well-innervated by sympathetic efferents, and their neurotransmitter noradrenaline was reported to modulate a variety of immune functions by binding to adrenergic receptors on immune cells (3)(4)(5)(6). Conversely, the immune system appears to influence the activity of sympathetic neurons locally and centrally by releasing cytokines that bind to receptors on neuronal and/or non-neuronal cells (7)(8)(9)(10).…”