Summary
1. During the course of studies directed to determine the transport of Angiotensin II AT2 receptors in the rat brain, we found that stab wounds to the brain revealed a binding site recognized by the AT2 receptor ligand CGP42112 but not by Angiotensin II.
2. We localized this novel site to macrophages/microglia associated with physical or chemical injuries of the brain.
3. The non-Angiotensin II site was also highly localized to inflammatory lesions of peripheral arteries.
4. In rodent tissues, high binding expression was limited to the spleen and to circulating monocytes. A high-affinity binding site was also characterized in human monocytes.
5. Lack of affinity for many ligands binding to known macrophage receptors indicated the possibility that the non-Angiotensin II CGP42112 binding corresponds to a novel site.
6. CGP42112 enhanced cell attachment to fibronectin and collagen and metalloproteinase-9 secretion from human monocytes incubated in serum-free medium but did not promote cytokine secretion.
7. When added in the presence of lipopolysaccharide, CGP42112 reduced the lipopolysaccharide-stimulated secretion of the pro-inflammatory cytokines TNF-α, IL-1, IL-1 ß, and IL-6, and increased protein kinase A.
8. Molecular modeling revealed that a CGP42112 derivative was selective for the novel macrophage site and did not recognize the Angiotensin II AT2 receptor.
9. These results demonstrate that CGP42112, previously considered as a selective Angiotensin II AT2 ligand, recognizes an additional non-Angiotensin II site different from AT2 receptors.
10. Our observations indicate that CGP42112 or related molecules could be considered of interest as potential anti-inflammatory compounds.
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This study is supported by the Division of Intramural Research Programs, National Institute of Mental Health, NIH, DHHS.
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Saavedra, J.M., Pavel, J. The Discovery of a Novel Macrophage Binding Site. Cell Mol Neurobiol 26, 507–524 (2006). https://doi.org/10.1007/s10571-006-9044-x
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DOI: https://doi.org/10.1007/s10571-006-9044-x