Interferon-gamma, tumor necrosis factor-alpha, and transforming growth factor-beta inhibit cyclic AMP-induced Schwann cell differentiation

Schwann cells differentiate in vivo in response to contact with axons, and cAMP simulates some of these aspects of differentiation in vitro, particula rly morphologic changes and expression of certain phenotypic molecules. Unf ractionated inflammatory cytokines inhibit cAMP-induced Schwann cell expres sion of galactolipids (Gal). We sought to identify which cytokines were res ponsible for this inhibition and to determine whether other phenotypic indi cators of Schwann cell differentiation were also affected. Neonatal rat Sch wann cells were incubated in vitro with 1 mM 8 Bromo cAMP (8 Br cAMP) with or without the addition of interleukin-1 alpha (IL-1 alpha), IL-1 beta, IL- 2, IL-6, tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gam ma), or transforming growth factor-beta (TGF-beta). Cells were then examine d for morphologic changes and for expression of surface Gal and low-affinit y nerve growth factor receptor (NGFRp75), employing indirect immunofluoresc ence. 8 Br cAMP induced Schwann cell upregulation of Gal, downregulation of NGFRp75, and the cells became enlarged and somewhat amorphous and irregula r in appearance. Cells treated with IFN-gamma or TNF-alpha alone were more bipolar and more evenly distributed on coverslips than were control cells, whereas TGF-beta alone induced elongated cells often in a swirling pattern. None of the cytokines alone induced upregulation of Gal or downregulation of NGFRp75. TNF-alpha, IFN-gamma, and TGF-beta inhibited the 8 Br cAMP-indu ced morphologic changes, as well as the upregulation of Gal and downregulat ion of NGFRp75. The other cytokines had no effects on Gal or NGFRp75 expres sion. Thus, these three cytokines, which are present in inflammatory lesion s in the peripheral nervous system, are capable of inhibiting Schwann cell differentiation. (C) 2001 Wiley-Liss, Inc.