|Figure 1. Confocal pseudocolor image of GDNF and GDNF receptor alpha 1 (GFR alpha 1) labeling in rat dorsal root ganglia. GDNF is labeled with R&D Systems' goat anti-rat GDNF (Catalog # AF-212-NA) and staining visualized with secondary FITC-conjugated antibodies (green). GFR alpha 1 is labeled with R&D Systems' biotinylated goat anti-rat GFR alpha 1 (Catalog # BAF560) and staining visualized with secondary streptavidin-Cy3 antibodies (red).|
Cytokines play an important role in neuronal development as well as in inflammation.1,2 Those attracting the most attention for their therapeutic potential include IL-6, TGF-beta, TNF and the neurotrophic factors including, nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), neurotrophin 3-6 (NT-3-6) and glial cell-line derived neurotrophic factor (GDNF).
IL-6 is well known as a mediator of the immune response.3-5 It also regulates cells of the central nervous system (CNS). In situ hybridization revealed mRNA of IL-6 and its receptor in several areas of the brain, including the hippocampus, striatum, hypothalamus, neocortex, cerebellum and brain stem.6-9 While IL-6 levels in the adult CNS are low, they are elevated after injury and inflammation. Elevated levels of IL-6 also are associated with several neurological disorders, including CNS infection, traumatic brain injury,10 Multiple Sclerosis, Alzheimer's disease and Parkinson's disease.11
Elevated levels of IL-1 and TNFs occur after head injury and IL-1 can induce expression of alpha 1-antichymo trypsin,12 a possible pathological chaperone in promoting polymerization of beta-amyloid protein into filaments. This implicates IL-1 in the region-specific production of mature amyloid filament in Alzheimer's disease.
TGF-beta13 and several members of the TGF-beta superfamily, including bone morphogenetic proteins (BMPs), growth and differentiation factors (GDFs) and glial cell-line derived neurotrophic factors (GDNF), may play key roles in the development, repair and survival of neurons. Increased levels of TGF-beta 1 mRNA and changes in its distribution patterns have been observed in various regions of the brain after ischemic insult, where it may influence the post-ischemic neuron-glial interaction.14 Possible synthesis of TGF-beta in the CNS was inferred by high levels of TGF-beta in the cerebrospinal fluid of patients with multiple sclerosis in remission relative to patients in active phase.15
BMP mRNA has been detected in the nervous system throughout the stages of development. BMP-2 and BMP-4 are expressed in the ectoderm and inhibit neuralization.16-18 In addition to their role in development, these proteins have shown neurotrophic effects on various neuronal cells. BMP-2, -4 and -7 induce expression of adrenergic sympathetic neurons,19 and BMP-7, in the presence of NGF, promotes selective dendritic outgrowth from sympathetic neurons.20
GDNF is well known for its survival and promoting effects on dopaminergic neurons.21,22 GDF-5 has shown neurotrophic effects on dopaminergic neurons and dorsal root ganglionic neurons in vitro.23,24 GDF-1 and GDF-10 mRNA have been detected in several regions of the brain as well.25,26 Their neurotrophic effects with other neurotrophic factors, including BDNF, NT-3-6, and NGF, may provide valuable information for improvement of the treatment of neurological diseases.
Many questions regarding the sources, targets and functions of these cytokines and cellular and molecular mechanisms of their actions still remain unanswered. The correlation of levels of certain cytokines with neurological disorders opens a possibility that administration of cytokines or their antibodies may improve the treatment of several neurological disorders.