Transforming growth factor-beta 1 induces transforming growth factor-beta 1 and transforming growth factor-beta receptor messenger RNAs and reduces complement C1qB messenger RNA in rat brain microglia

Transforming growth factor-beta1 is a multifunctional peptide with increase d expression during Alzheimer's disease and other neurodegenerative conditi ons which involve inflammatory mechanisms. We examined the autoregulation o f transforming growth factor-beta1 and transforming growth factor-beta rece ptors and the effects of transforming growth factor-beta1 on complement C1q in brains of adult Fischer 344 male rats and in primary glial cultures. Pe rforant path transection by entorhinal cortex lesioning was used as a model for the hippocampal deafferentation of Alzheimer's disease. In the hippoca mpus ipsilateral to the lesion, transforming growth factor-beta1 peptide wa s increased >100-fold; the messenger RNAs encoding transforming growth fact or-beta1, transforming growth factor-beta type I and type II receptors were also increased, but to a smaller degree. In this acute lesion paradigm, mi croglia are the main cell type containing transforming growth factor-beta1, transforming growth factor-beta type I and II receptor messenger RNAs, sho wn by immunocytochemistry in combination with in situ hybridization. Autore gulation of the transforming growth factor-beta1 system was examined by int raventricular infusion of transforming growth factor-beta1 peptide, which i ncreased hippocampal transforming growth factor-beta1 messenger RNA levels in a dose-dependent fashion. Similarly, transforming,orowth factor-beta1 in creased levels of transforming growth factor-beta1 messenger RNA and transf orming growth factor-beta type II receptor messenger RNA (IC50, 5 pM) and i ncreased release of transforming growth factor-beta1 peptide from primary m icroglia cultures. Interactions of transforming growth factor-beta1 with co mplement system gene expression are also indicated, because transforming gr owth factor-beta1 decreased C1qB messenger RNA in the cortex and hippocampu s, after intraventricular infusion, and in cultured glia. These indications of autocrine regulation of transforming growth factor-beta1 in the rodent brain support a major role of microglia in neural activities of transformin g growth factor-beta1 and give a new link between transforming growth facto r-beta1 and the complement system. The auto-induction of the transforming g rowth factor-beta1 system has implications for transgenic mice that overexp ress transforming growth factor-beta1 in brain cells and for its potential role in amyloidogenesis. (C) 2000 IBRO. Published by Elsevier Science Ltd. All rights reserved.