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Volume 17, Number 14, Issue of July 15, 1997 pp. 5305-5315
Copyright ©1997 Society for Neuroscience

Neurons Promote Macrophage Proliferation by Producing Transforming Growth Factor-2

Received Jan. 27, 1997; revised April 24, 1997; accepted May 5, 1997.

Alexandre Dobbertin¹, Peter Schmid², Michèle Gelman¹, Jacques Glowinski¹, and Michel Mallat¹

¹ Institut National de la Santé et de la Recherche Médicale U 114, Chaire de Neuropharmacologie, Collège de France, 75231 Paris Cedex 05, France, and ² Ciba-Geigy Limited, CH-4002 Basel, Switzerland

The infiltration of bone marrow-derived macrophages into the CNS contributes to growth and reactions of microglia during development or after brain injury. The proliferation of microglial cells is stimulated by colony-stimulating factor 1 (CSF-1), an astrocyte-produced growth factor that acts on mononuclear phagocytes. In the present study, we have shown, using an in vitro model system, that rodent neurons obtained from the developing cerebral cortex produce a soluble factor that strongly enhances the proliferation of macrophages cultured in the presence of CSF-1. Both macrophages isolated from the developing brain and those from the adult bone marrow were stimulated. Kinetic analyses of [³H]thymidine incorporation into macrophages indicated that their response to the neuron-derived factor involved a shortening of the cycle of proliferating cells. The effect of neurons on macrophages was blocked in the presence of antibodies neutralizing transforming growth factor-2 (TGF-2), whereas recombinant TGF-2 stimulated macrophage proliferation in the presence of CSF-1. Neuronal secretion of TGF-2 was confirmed by reverse transcription-PCR detection of TGF-2 transcripts and immunodetection of the protein within neurons and in their culture medium. In situ hybridization and immunohistochemical experiments showed neuronal expression of TGF-2 in sections of cerebral cortex obtained from 6-d-old rats, an age at which extensive developmental recruitment of macrophages occurs in this cerebral region. Altogether, our results provide direct evidence that neurons have the capacity to promote brain macrophage proliferation and demonstrate the role of TGF-2 in this neuronal function.

Key words: microglia; bone marrow-derived macrophage; neuron; colony-stimulating factor 1; transforming growth factor-; rat

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