Activation of the renin-angiotensin system (RAS) is a major factor contributing to the pathophysiology of cardiovascular disease (CVD). Blockade of the RAS with angiotensin receptor blockers (ARBs) has been a standard treatment for CVD. Activation of angiotensin II type 2 receptor (AT2) and angiotensin I-converting enzyme 2 (ACE2) contribute to the cardioprotective effects of ARBs. Both AT2 and ACE2 counteract the vasoconstrictor and pro-inflammatory effects of angiotensin II. However, the possible interaction between AT2 and ACE2 has never been established. Tumor necrosis factor (TNFα) is a cytokine involved in angiotensin II signaling and promotes the inflammatory response via NF-κB. We hypothesized that activation of AT2 increases ACE2, thereby preventing TNFα-stimulated intercellular adhesion molecule-1 (ICAM-1) expression via inhibition of NF-κB. Human coronary artery endothelial cells were pretreated with AT2 antagonist PD123319 or ACE2 inhibitor DX-600, and then stimulated with TNFα in the presence or absence of AT2 agonist CGP42112A. ACE2 mRNA was measured by real-time RT-PCR. ACE2 activity was measured using a Fluorimetric Kit. ICAM-1 and phospho-inhibitory κB (p-IκB) were measured by Western Blot. Activation of AT2 with CGP42112A increased ACE2 mRNA by 1.82 ± 0.09 fold (p<0.01) and ACE2 activity from 0.61 ± 0.05 to 0.95 ± 0.03 (pg/μl/h/μg protein) (p<0.01). This effect was diminished by inhibition of AT2 or ACE2. ICAM-1 expression was almost undetectable in untreated cells but greatly increased by TNFα. Activation of AT2 reduced TNFα-induced ICAM-1 expression by 47% (from control value of 1 to 0.53 units) ± 5% (p<0.01), which was diminished by AT2 antagonist or ACE2 inhibitor. We also found that TNFα increased p-IκB by 7.46 ± 0.51 fold (p<0.01) compared to untreated cells and this effect was diminished by AT2 activation. Furthermore, ACE2 inhibitor blunted the effects of AT2 on TNFα-induced p-IκB expression. Our findings suggest that stimulation of AT2 reduces TNFα-induced ICAM-1 expression, which is partly through ACE2-mediated inhibition of NF-κB. Perspective: understanding the mechanisms underlying AT2-mediated anti-inflammatory effects could lead to new therapeutic strategies such as specific activation of AT2 and/or ACE2.