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Immune parameters were analyzed in peripheral blood mononuclear cells (PBMC) and cervical mucosa biopsy specimens of human immunodeficiency virus (HIV)-seronegative women sexually exposed to HIV (exposed seronegative [ESN]), HIV-infected women, and healthy women without HIV exposure. HIV was not detected in PBMC or cervical mucosa biopsy specimens of ESN women. However, interleukin (IL)-6, IL-10, IL-12, interferon (IFN)-gamma, and tumor necrosis factor (TNF)-alpha and -beta mRNA were elevated in PBMC and cervical mucosa biopsy specimens of ESN and HIV-infected women; CCR5 and CXCR4 mRNA were augmented in cervical mucosa biopsy specimens, but not in PBMC, of ESN and HIV-infected women; HIV-specific IFN-gamma-secreting cells were detected in vaginal washes of ESN and HIV-infected women; and phenotypic alterations were present in PBMC of ESN women. These results suggest that active HIV infection is not required for T cell activation; immune alterations occur in women in whom HIV infection cannot be detected virologically or clinically.

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Endothelins (ETs), potent vasoconstricting peptides, are produced by macrophages upon stimulation and may participate in the amplification or regulation of the inflammatory response. However, it is not clear whether ETs can act in an autocrine manner on macrophages and which role they play in relationship with other cytokines. To address these issues, we studied the effects of ETs on the production of inflammatory cytokines by mouse peritoneal macrophages or by a retrovirus-transformed microglial cell line. Here, we report that ET-2, but not ET-1 or ET-3, is able to stimulate the production of interleukin-1 (IL-1) and interleukin-6 (IL-6) by peptone-elicited mouse macrophages (pMO). In contrast, ET-3 and ET-1, but not ET-2, are active on microglial cells. No tumour necrosis factor-alpha (TNF-alpha) or nitric oxide (NO) were detected in the supernatants of ET-stimulated cultures. The activity of ET-2 on pMO was time and dose dependent and was inhibited by the addition of ETA and ETB receptor antagonists, BQ123 and IRL1038, respectively. In addition, when pMO were stimulated by interferon-gamma (IFN-gamma) in the presence of ET-2, a significant inhibition of IL-6 and IL-1 production was observed compared with the effects of the same doses of IFN-gamma or ET-2 used separately. The inhibition was specifically due to the activity of ET-2, since it was reversed by the addition of BQ123 or IRL1038. Similar results were seen when the content of NO in the supernatants of pMO stimulated by IFN-gamma plus ET-2 was evaluated. These results suggest that ETs may possess both a pro-inflammatory action on macrophages from different tissues and a regulatory activity on IFN-gamma.