GLIAL CELL-SPECIFIC MECHANISMS OF TGF-BETA-1 INDUCTION BY IL-1 IN CEREBRAL-CORTEX

Transforming growth factor beta-1 (TGF-beta1) immunoreactive product (IRP) has recently been detected in autopsied brains of individuals who died with central nervous system diseases and/or fever but not in normal individuals or in normal rodent brain. However, the mechanism(s) of induction of TGF-beta1 in brain and the identity of cells expressing TGF-beta1 need to be understood before a role, if any, for this potent pleiotropic cytokine in neuropathogenesis can be discerned. Towards this end we determined that IL-1 stimulated the production of TGF-beta1 IRP in cells and TGF-beta1 activity in culture fluids of all glial cells, astrocytes, microglial cells, and oligodendrocytes, derived from neonatal rat cortex and grown in cell type-enriched cultures. TGF-beta1 production in vitro varied with the cell type and isoform of IL-1. Oligodendrocytes produced the most and astrocytes the least amount of TGF-beta1. IL-1alpha stimulated TGF-beta1 production in all glial cell types, whereas IL-1beta did not. In vivo, TGF-beta1 IRP was detected in human tissues from cerebral frontal cortex and subcortical white matter only when interleukin-1 (IL-1) was elevated in the same tissues. Moreover, the amount of detectable TGF-beta1 was positively correlated with the amount of detectable IL-1 (rho = 0.605; P = 0.003), as determined by morphometry. Double-labelling of cells for their phenotypic markers and expression of TGF-beta1 indicated that all glial cells, but not neurons, expressed TGF-beta1. IL-1alpha and IL-1beta IRPs were also detected in all three glial cell types, most frequently in astrocytes and least frequently in microglial cells. The cells containing both cytokine IRPs were also detected. These results indicate that TGF-beta1 may be induced by IL-1 in all glial cells of the frontal cortex, by both autocrine and paracrine mechanisms.