Opposite effect of angiotensin receptor blockade on CXCL8 production and CXCR1/2 expression of angiotensin II-treated THP-1 monocytes

Abstract

Interleukin-8 (IL-8) or CXCL8 is a potent chemotactic factor that is involved in atherogenesis. IL-8 mediates its pre-inflammatory effects through interaction with CXCR1 and CXCR2. In the present study, we investigated the effects of angiotensin II (Ang II) on IL-8 synthesis and CXCR1/CXCR2 expression of THP-1 monocytes. IL-8 was measured in the culture medium using ELISA. Expression of chemokine receptors CXCR1 and CXCR2 was evaluated by flow cytometry. Results demonstrated that the addition of Ang II increased IL-8 production in the THP-1 monocytes. The Ang II type 1 receptor blocker (ARB) losartan significantly blocked Ang II-induced IL-8 production. Notably, losartan blocked LPS-induced IL-8 production by THP-1 monocytes and produced a small but statistically significant reduction of baseline IL-8 production of naïve THP-1 cells. Losartan also produced a statistically significant increase of fluorescence intensity of naïve CXCR1- and CXCR2-positive THP-1 monocytes, probably as a negative feedback effect secondary to IL-8 downregulation. In conclusion, we demonstrated that Ang II increased IL-8 production by THP-1 monocytes. Losartan significantly suppressed the latter effect, suggesting an AT-1 mediated pathway. Moreover, losartan suppressed the IL-8 production of naïve THP-1 monocytes and LPS-treated THP-1 monocytes, suggesting a broader spectrum of pleiotropic effects. Extrapolating this in vitro observation to in vivo pathways, we propose Ang II-induced IL-8 production by monocytes as another pre-atherogenic potential of Ang II that can be effectively blocked by the AT1 receptor blockade.