CGP-42112 partially activates human monocytes and reduces their stimulation by lipopolysaccharides.
CGP 42112, a high-affinity ligand for angiotensin II AT2 receptors, binds to rat macrophage/microglia lacking AT2 receptors. Here we report that CGP-42112 binds to human monocytes and exerts specific effects. Binding studies revealed a single site, highly specific for CGP-42112, not displaceable by angiotensin II, angiotensin fragments, tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-4, IL-10, transforming growth factor-beta, or lipopolysaccharide (LPS). Incubation of purified human monocytes in serum-free medium with CGP-42112 enhanced, in a dose-dependent manner, cell attachment to fibronectin and collagen-coated dishes as well as matrix metalloproteinase-9 secretion. CGP-42112 did not promote cytokine secretion. In contrast, when added in the presence of low doses of LPS, CGP-42112 reduced the LPS-stimulated secretion of TNF-alpha, IL-1 alpha, IL-1 beta, and IL-6 without affecting IL-10 and decreased the LPS-stimulated matrix metalloproteinase-9 activity. Additionally, CGP-42112 inhibited the increase in protein kinase A activity produced by LPS. Our results indicate that CGP-42112 may modulate monocyte activation through binding to a novel receptor.
Egidy
G
G
Section on Pharmacology, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland 20892, USA.
Friedman
J
J
Viswanathan
M
M
Wahl
L M
LM
Saavedra
J M
JM
D000818:Animals; D001667:Binding, Competitive; D002448:Cell Adhesion; D002478:Cells, Cultured; D017364:Collagenases / Q000096:biosynthesis; D016895:Culture Media, Serum-Free; D016207:Cytokines / Q000096:biosynthesis*; D015232:Dinoprostone / Q000378:metabolism; D006801:Humans; D007375:Interleukin-1 / Q000096:biosynthesis; D016753:Interleukin-10 / Q000096:biosynthesis; D015850:Interleukin-6 / Q000096:biosynthesis; D008070:Lipopolysaccharides / Q000494:pharmacology*; D020780:Matrix Metalloproteinase 9; D009000:Monocytes / Q000187:drug effects / Q000276:immunology / Q000502:physiology*; D009842:Oligopeptides / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin / Q000187:drug effects / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D016895:Culture Media, Serum-Free; D016207:Cytokines; D007375:Interleukin-1; D015850:Interleukin-6; D008070:Lipopolysaccharides; D009842:Oligopeptides; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin; D014409:Tumor Necrosis Factor-alpha; C060894:CGP 42112A; D016753:Interleukin-10; D017364:Collagenases; D020780:Matrix Metalloproteinase 9; D015232:Dinoprostone