J. Exp. Med., Volume 188, Number 4, August 17, 1998 635-649

Interleukin 3 Prevents Delayed Neuronal Death in the Hippocampal CA1 Field

By Tong-Chun Wen,^* Junya Tanaka, Hui Peng,^* Junzo Desaki,^* Seiji Matsuda,^* Nobuji Maeda, Hiroko Fujita,^* Kohji Sato,^* and Masahiro Sakanaka^*

From the ^* Department of Anatomy and the  Department of Physiology, Ehime University School of Medicine, Shigenobu, Ehime, 791-0295 Japan

In the central nervous system, interleukin (IL)-3 has been shown to exert a trophic action only on septal cholinergic neurons in vitro and in vivo, but a widespread distribution of IL-3 receptor (IL-3R) in the brain does not conform to such a selective central action of the ligand. Moreover, the mechanism(s) underlying the neurotrophic action of IL-3 has not been elucidated, although an erythroleukemic cell line is known to enter apoptosis after IL-3 starvation possibly due to a rapid decrease in Bcl-2 expression. This in vivo study focused on whether IL-3 rescued noncholinergic hippocampal neurons from lethal ischemic damage by modulating the expression of Bcl-x_L, a Bcl-2 family protein produced in the mature brain. 7-d IL-3 infusion into the lateral ventricle of gerbils with transient forebrain ischemia prevented significantly hippocampal CA1 neuron death and ischemia-induced learning disability. TUNEL (terminal deoxynucleotidyltransferase-mediated 2'-deoxyuridine 5'-triphosphate-biotin nick end labeling) staining revealed that IL-3 infusion caused a significant reduction in the number of CA1 neurons exhibiting DNA fragmentation 7 d after ischemia. The neuroprotective action of IL-3 appeared to be mediated by a postischemic transient upregulation of the IL-3R  subunit in the hippocampal CA1 field where IL-3R was barely detectable under normal conditions. In situ hybridization histochemistry and immunoblot analysis demonstrated that Bcl-x_L mRNA expression, even though upregulated transiently in CA1 pyramidal neurons after ischemia, did not lead to the production of Bcl-x_L protein in ischemic gerbils infused with vehicle. However, IL-3 infusion prevented the decrease in Bcl-x_L protein expression in the CA1 field of ischemic gerbils. Subsequent in vitro experiments showed that IL-3 induced the expression of Bcl-x_L mRNA and protein in cultured neurons with IL-3R and attenuated neuronal damage caused by a free radical-producing agent FeSO₄. These findings suggest that IL-3 prevents delayed neuronal death in the hippocampal CA1 field through a receptor-mediated expression of Bcl-x_L protein, which is known to facilitate neuron survival. Since IL-3R in the hippocampal CA1 region, even though upregulated in response to ischemic insult, is much less intensely expressed than that in the CA3 region tolerant to ischemia, the paucity of IL-3R interacting with the ligand may account for the vulnerability of CA1 neurons to ischemia.

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