Expression of growth differentiation factor‐15/ macrophage inhibitory cytokine‐1 (GDF‐15/MIC‐1) in the perinatal, adult, and injured rat brain

Abstract

We and others have recently cloned a new member of the transforming growth factor-beta superfamily, growth differentiation factor-15/ macrophage inhibitory cytokine-1 (GDF-15/MIC-1). Using in situ hybridization and immunohistochemistry, we determined the distribution of GDF-15/MIC-1 mRNA and protein in the perinatal and cryolesioned adult rat brain. The choroid plexus epithelium of all ventricles represents the site of strongest and almost exclusive mRNA expression in the normal perinatal and adult brain. The newborn rat brain reveals GDF-15/MIC-1 immunoreactivity (ir) in ependymal cells lining the ventricles, in the striatal subventricular zone, and in populations of nonneural cells of the thalamic/hippocampal lamina affixa, in addition to that in the choroid plexus. Unilateral cryogenic cortical lesioning induced a significant increase of GDF-15/MIC-1 mRNA expression and ir at the lesion site and expression in presumed neurons within the dorsal thalamic area. At the lesion site, GDF-15/MIC-1-producing cells showed immuncytochemical features of neurons, macrophages, and activated microglial cells. Fluorescent microscopy revealed both intra- and extracellular GDF-15/MIC-1 ir. Up-regulation of GDF-15/MIC-1 in activated macrophages (Mstraight phi) is also supported by RT-PCR, ICC, and Western blot experiments showing pronounced induction of GDF-15/MIC-1 expression (mRNA and protein) in retinoic acid/phorbol ester-stimulated human M phi. Our data suggest that 1) GDF-15/MIC-1 is secreted into the cerebrospinal fluid and 2) in the newborn brain may penetrate through the ependymal lining and act on developing neurons and/or glial cells. As a constituent of cells in the lamina affixa, the protein might be involved in the regulation of mesenchyme-epithelial interactions. Finally, GDF-15/MIC-1 may also act within the antiinflammatory cytokine network activated in CNS lesions.

Growth Differentiation Factor-15 Prevents Low Potassium-induced Cell Death of Cerebellar Granule Neurons by Differential Regulation of Akt and ERK Pathways

“…With regard to GDF-15, a pro-apoptotic role in several cell lines has been suggested (48 -51). Moreover, our observation that GDF-15 is robustly induced in lesioned cortical neurons (16) can be interpreted in terms of both an anti-or pro-apoptotic role. To clarify this, we started to analyze the effect of GDF-15 and underlying mechanisms on neuronal apoptosis using the well established CGN model (18).…”

“…At this point, it is not clear whether other types of central nervous system neurons are affected by GDF-15. In a previous study, we had also shown that GDF-15 protein is up-regulated in cortical neurons subsequent to a cold lesion (16). This may indicate functions of the protein in neurons affected by injury and suggest a role of GDF-15 in the execution of either survival or cell death programs.…”

Nonsteroidal Anti-inflammatory Drug-activated Gene (NAG-1/GDF15) Expression Is Increased by the Histone Deacetylase Inhibitor Trichostatin A

“…Moreover, NAG-1 is induced by several nonsteroidal anti-inflammatory drugs and other drugs known to have anti-tumorigenic and pro-apoptotic activities (11, 12). In the brain, NAG-1 is expressed in epithelial cells of the choroid plexus and secreted into the cerebral spinal fluid and is reported to function as both a neurotrophic and a neuroprotective factor for midbrain dopaminergic neurons in vivo and in vitro (13,14). Recently, we generated NAG-1 transgenic mice (Cre/NAG-1 Tg/Lox ), which express human NAG-1 in all tissues (15).…”

Macrophage inhibitory cytokine-1 is associated with cognitive impairment and predicts cognitive decline - the Sydney Memory and Aging Study

“…Within the central nervous system (CNS), MIC-1/GDF15 is expressed by the choroid plexus and secreted into the cerebrospinal fluid. It is up-regulated as part of the antiinflammatory cytokine network within the CNS in response to injury (Schober et al, 2001), and in this role, it is directly neurotrophic and possibly neuroprotective (Strelau et al, 2000). Cerebrospinal fluid (CSF) concentrations of MIC-1/GDF15 are relatively elevated in human neuronal injury (B. J.…”