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The Journal of Neuroscience, November 3, 2004, 24(44):9944-9952; doi:10.1523/JNEUROSCI.2856-04.2004

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Cellular/Molecular
Macrophage Migration Inhibitory Factor: An Intracellular Inhibitor of Angiotensin II-Induced Increases in Neuronal Activity

Chengwen Sun,¹ Hongwei Li,¹ Lin Leng,² Mohan K. Raizada,¹ Richard Bucala,² and Colin Sumners¹

¹Department of Physiology and Functional Genomics and McKnight Brain Institute, University of Florida, Gainesville, Florida 32610-0274, and ²Yale University School of Medicine, New Haven, Connecticut 06520-8031

Angiotensin II (Ang II) elicits Ang II type 1 receptor (AT1-R)-mediated increases in neuronal firing within the hypothalamus and brainstem that are ultimately responsible for physiological actions such as increased blood pressure and fluid intake. Although there is a growing literature on the intracellular mechanisms that mediate the actions of Ang II via AT1-R in neurons, little is known about the mechanisms that diminish or "switch-off" the neuronal chronotropic action of Ang II. In the present study, we identified macrophage migration inhibitory factor (MIF) as an intracellular inhibitor of the actions of Ang II in neurons. The evidence is as follows. First, Ang II, acting via AT1-R, increases the intracellular levels of MIF in neurons cultured from rat hypothalamus and brainstem. Second, elevation of intracellular MIF by Ang II prevents further chronotropic actions of this peptide. Third, intracellular application of exogenous recombinant MIF abolishes the Ang II-induced chronotropic action in neurons. Finally, intracellular application of the MIF peptide fragment MIF-(50-65), which harbors the thiol oxidoreductase property of the MIF molecule, mimics the inhibitory actions of MIF on Ang II-stimulated neuronal firing. Thus, this study is the first to demonstrate the existence of an intracellular negative regulator of Ang II-induced actions in neurons and indicates that MIF may act as a physiological brake for the chronotropic effects of Ang II in rat neurons.

Key words: angiotensin II; macrophage migration inhibitory factor; neuron; firing rate; thiol-protein oxidoreductase; reactive oxygen species

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Received April 15, 2004; revised September 24, 2004; accepted September 27, 2004.

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