A cytokine switch induced by human seminal plasma: an immune modulation with implications for sexually transmitted...

The immunosuppressive activity of human seminal plasma may be one factor in the aetiology of sexually transmitted disease and could be particularly important for the spread of human immunodeficiency virus (HIV). The advent of virus that can preferentially infect Langerhans cells of the genital mucosa underscores the relevance of seminal plasma effects. Virally infected cells are eradicated by the killing activity of T cells and natural killer (NK) cells and this cytotoxicity is stimulated by IL-12 (previously known as natural killer cell stimulatory factor) and partly inhibited by IL-10 (previously known as cytokine synthesis inhibitory factor). We have examined the effects of human seminal plasma on the production of these key cytokines. Cytokine production was measured in rapidly diluted, fresh, lipopolysaccharide (LPS)-stimulated, whole blood since this provided leukocytes with minimal exposure to prostaglandin. Prostaglandin concentrations and cytokine release were measured by ELISA. Addition of human seminal plasma diluted up to 100,000 times (0.001%) to blood cell cultures led to a marked increase in the IL-10/IL-12 ratio (P <0.02). A dose-dependent increase in the ratio was observed in five separate experiments, from a control value of 1 (no seminal plasma) to a mean value of 80 (1% seminal plasma). This cytokine switch was also seen when seminal plasma was substituted by pure prostaglandin E (PGE) and 19-OH PGE (the main prostaglandin constituent of human seminal plasma). Lipid-extracted seminal plasma was considerably less active at high dilutions than whole seminal plasma at the same dilution. However, its activity could be restored by the addition of synthetic PGE and 19-hydroxy PGE. A stimulation of IL-10 and a decrease in IL-12 in host-defence cells of the lower female reproductive tract will seriously affect the ability of cytotoxic T cells and NK cells to recognise and destroy virally infected cells. In addition, the stimulation of IL-10 will inhibit the release of the anti-HIV activity from CD8+ve cells. The cytokine switch reported here, activated by semen deposition, would exercise a key inhibitory control over vital immune defences in the lower genital tract, with ablation of cell-mediated responses and immunosurveillance.