Inflammatory/demyelinating diseases of the peripheral (PNS) and central (CNS) nervous system constitute an important group of disorders including Guillain-Barre syndrome, chronic inflammatory demyelinating polyneuropathy and multiple sclerosis. Inflammatory cells are also present and are likely to be involved in traumatic and infectious diseases of the PNS and CNS. There is recent evidence that soluble mediators, or cytokines, secreted by inflammatory cells have important interactions with glial cells, as demonstrated in experimental models, in vitro studies and patients with these neurologic diseases. this project examines the hypothesis that cytokines, especially interleukin 1 (IL-1), are important modifiers of Schwann cell proliferation and differentiation, key steps in the process of PNS repair and remyelination.
The specific aims focus on three central issues, (1) the role of cytokines in Schwann cell proliferation, (2) the presence of IL-1 receptors on Schwann cells and their ability to synthesize and secrete IL-1alpha and IL-1beta, and (3) the influence of IL-1 and other monokines on the expression of myelin-associated proteins and lipids. We have found that cytokines stimulate Schwann cells to proliferate in vitro, and antibodies to IL-1 inhibit this proliferation, supporting the hypothesis that IL-1 is a co-mitogen for Schwann cells.
Specific aim 1 investigates whether other monokines act as mitogens and/or co-mitogens for Schwann cells, and whether age or state of differentiation of the Schwann cells alters the proliferative response. Emphasis will be on the monokines IL- 1alpha, IL-1beta, IL-6, tumor necrosis factor (TNF), and transforming growth factor (TGF) because of the importance of cells of the monocyte/macrophage lineage in inflammatory lesions.
Specific aim 2 examines the possibility that IL-1 serves an autocrine function in Schwann cells. Thus we will confirm that Schwann cells synthesize and secrete IL-1, and determine the amounts of the two isoforms produced, employing immunologic and molecular biologic techniques. The presence of IL-1 receptors will be examined with ligand-binding and immunofluorescence methods. The effects of age and differentiation on expression of the IL-1 isoforms and their receptors will be determined.
Specific aim 3 will investigate whether cytokines influence expression and synthesis of myelin-associated lipids and proteins.
