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Macrophages have an important role in the pathogenesis of hypertension and associated end-organ damage via the activation of the Toll-like receptors, such as Toll-like receptor-4 (TLR4). Accumulating evidence suggests that the angiotensin AT2 receptor (AT2R) has a protective role in pathological conditions involving inflammation and tissue injury. We have recently shown that AT(2)R stimulation is renoprotective, which occurs in part via increased levels of anti-inflammatory interleukin-10 (IL-10) production in renal epithelial cells; however, the role of AT(2)R in the inflammatory activity of macrophages is not known. The present study was designed to investigate whether AT(2)R activation stimulates an anti-inflammatory response in TLR4-induced inflammation. The effects of the anti-inflammatory mechanisms that occurred following pre-treatment with the AT(2)R agonist Compound 21 (C21) (1 μmol ml(-1)) on the cytokine profiles of THP-1 macrophages after activation by lipopolysaccharide (LPS) (1 μg ml(-1)) were studied. The AT(2)R agonist dose-dependently attenuated LPS-induced tumor necrosis factor-α (TNF-α) and IL-6 production but increased IL-10 production. IL-10 was critical for the anti-inflammatory effects of AT(2)R stimulation because the IL-10-neutralizing antibody dose-dependently abolished the AT(2)R-mediated decrease in TNF-α levels. Further, enhanced IL-10 levels were associated with a sustained, selective increase in the phosphorylation of extracellular signal-regulated kinase (ERK1/2) but not p38 mitogen-activated protein kinase (MAPK). Blocking the activation of ERK1/2 before C21 pre-treatment completely abrogated this increased IL-10 production in response to the AT(2)R agonist C21, while there was a partial reduction in IL-10 levels following the inhibition of p38. We conclude that AT(2)R stimulation exerts a novel anti-inflammatory response in THP-1 macrophages via enhanced IL-10 production as a result of sustained, selective ERK1/2 phosphorylation, which may have protective roles in hypertension and associated tissue injury.

Angiotensin AT2 receptor stimulation is anti-inflammatory in lipopolysaccharide-activated THP-1 macrophages via increased interleukin-10 production