title: The discovery of a novel macrophage binding site.
abstract: 1. During the course of studies directed to determine the transport of Angiotensin II AT(2) receptors in the rat brain, we found that stab wounds to the brain revealed a binding site recognized by the AT(2) 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-alpha, IL-1, IL-1 beta, 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 AT(2) receptor. 9. These results demonstrate that CGP42112, previously considered as a selective Angiotensin II AT(2) ligand, recognizes an additional non-Angiotensin II site different from AT(2) receptors. 10. Our observations indicate that CGP42112 or related molecules could be considered of interest as potential anti-inflammatory compounds.
authors.affiliation: Section on Pharmacology, Division of Intramural Research Programs, National Institute of Mental Health, National Institutes of Health, Department of Health and Human Services, Bethesda 20892, USA. Saavedrj@mail.nih.gov
authors.forename: Juan M
authors.initials: JM
authors.lastname: Saavedra
authors.forename: Jaroslav
authors.initials: J
authors.lastname: Pavel
mesh_terms: D000804:Angiotensin II / Q000378:metabolism; D000818:Animals; D001665:Binding Sites; D015415:Biomarkers / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D001930:Brain Injuries / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000209:etiology / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism*; D044139:Receptor, Angiotensin, Type 2 / Q000737:chemistry* / Q000378:metabolism*; D013379:Substrate Specificity
chemical_list: D015415:Biomarkers; D044139:Receptor, Angiotensin, Type 2; D000804:Angiotensin II