Monocytes/macrophages play a critical role in the pathogenesis of human immunodeficiency virus (HIV) -infection, both as targets f or virus replication and sources of production of multifunctional cytokines. Endothelins, peptides with potent vasoconstricting activities, originally isolated from endothelial cells, are also produced and secreted by macrophages in a manner similar to that of other cytokines. In an attempt to explore the potential role of endothelins in HIV-infection, we investigated the effect of the HIV-1 envelope glycoprotein, gpl20, on monocytic endothelin-1 production. This glycoprotein has been identified as a potent stimulator of monokines such as TNF-alpha and interleukin-6, which have been implicated as potential mediators of HIV-encephalopathy. We found that gpl20, similar to LPS, stimulates the secretion of endothelin-1 as well as TNF-alpha from macrophages in a concentration-dependent manner. Using reverse transcriptase polymerase chain reaction (RT PCR), we found that circulating monocytes in HIV-infected individuals show a distinct expression of the endothelin-1 gene which is not detectable in healthy controls, indicating chronic activation of this gene in HIV-infection. In addition, cerebral macrophages in patients with HIV-encephalopathy were strongly positive for endothelin. Thus, monocytic endothelins appear to be stimulated during HIV-infection. Their potent vasoactive properties render them potential candidates for mediating alterations in the cerebral perfusion pattern associated with the AIDS dementia complex.
