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Originally published online as doi:10.1189/jlb.0405222 on October 4, 2005

Published online before print October 4, 2005
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(Journal of Leukocyte Biology. 2005;78:1204-1209.)
© 2005 by Society for Leukocyte Biology

Are chemokines the third major system in the brain?

Martin W. Adler*,{dagger},1 and Thomas J. Rogers*,{dagger},{ddagger}

* Center for Substance Abuse Research,
{ddagger} Fels Institute for Cancer Research and Molecular Biology,
{dagger} Department of Pharmacology, Temple University School of Medicine, Philadelphia, Pennsylvania

1 Correspondence: Center for Substance Abuse Research, Temple University School of Medicine, 3400 N. Broad Street, Philadelphia, PA 19140. E-mail: baldeagl{at}temple.edu

ABSTRACT

Chemokines are a family of small proteins involved in cellular migration and intercellular communication. Although the chemokines and their receptors are located throughout the brain, they are not distributed uniformly. Among the chemokines and their receptors that are arrayed disproportionately in glia and neurons are monocyte chemotactic protein-1/CC chemokine ligand 2 (CCL2), stromal cell-derived factor-1/CXC chemokine ligand 12 (CXCL12), fractalkine/CX3C chemokine ligand 1, interferon-{gamma}-inducible-protein-10/CXCL10, macrophage inflammatory protein-1{alpha}/CCL3, and regulated on activation, normal T cell expressed and secreted/CCL5. In the brain, they are found in the hypothalamus, nucleus accumbens, limbic system, hippocampus, thalamus, cortex, and cerebellum. The uneven distribution suggests that there may be functional roles for the chemokine "system," comprised of chemokine ligands and their receptors. In addition to anatomical, immunohistochemical, and in vitro studies establishing the expression of the chemokine ligands and receptors, there is an increasing body of research that suggests that the chemokine system plays a crucial role in brain development and function. Our data indicate that the chemokine system can alter the actions of neuronally active pharmacological agents including the opioids and cannabinoids. Combined with evidence that the chemokine system in the brain interacts with neurotransmitter systems, we propose the following hypothesis: The endogenous chemokine system in the brain acts in concert with the neurotransmitter and neuropeptide systems to govern brain function. The chemokine system can thus be thought of as the third major transmitter system in the brain.

Key Words: opioids • heterologous desensitization • neuromodulators • interneuronal communication




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