Regulation of vascular type 1 angiotensin receptors by cytokines

Although various cytokines are known to be expressed in atherosclerotic lesions, it is not known how these cytokines affect receptors for the peptide hormone angiotensin II (Ang II). We therefore examined the effects of interleukin-1 alpha (220 U/mL [10 ng/mL]), tumor necrosis factor-alpha (280 U/mL [100 ng/mL]), and interferon gamma (100 U/mL) on Ang II type 1 (AT1) receptors expressed in rat vascular smooth muscle cells. Treatment with interleukin-1 alpha caused a 1.4- to 1.7-fold increase in AT1 binding after 24 hours (P<.01) and a 2.3-fold increase in AT1 mRNA (P<.05). Tumor necrosis factor-alpha and interferon gamma did not cause a significant change in AT1 binding when administered alone but caused a 30% reduction in binding when administered together (P<.05). The maximal decrease in AT1 binding (60%, P<.01) was seen with the combination of interleukin-1 alpha with tumor necrosis factor-alpha and interferon gamma. Although the upregulation of AT1 by interleukin-1 alpha was unaffected by pretreatment of cells with N-monomethyl-L-arginine or indomethacin, downregulation of AT1 by interleukin-1 alpha combined with tumor necrosis factor-alpha/interferon gamma was inhibited by N-monomethyl-L-arginine (P<.01). Interleukin-1 alpha treatment enhanced Ang II-induced [3H]uridine incorporation, whereas treatment with interleukin-1 alpha combined with tumor necrosis factor-alpha/interferon gamma attenuated Ang II-induced [3H]uridine and [3H]leucine incorporation. These results demonstrate that interleukin-1 alpha upregulates AT1 receptors and enhances Ang II-stimulated hypertrophic responses. However, a combination of interleukin-1 alpha with tumor necrosis factor-alpha and interferon gamma downregulates AT1 receptors by a nitric oxide-dependent mechanism and reduces Ang II-stimulated trophic responses in vascular smooth muscle cells.