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

The immunosuppressive activity of human seminal plasma may be one factor inthe aetiology of sexually transmitted disease and could be particularlyimportant for the spread of human immunodeficiency virus (HIV). The adventof virus that can preferentially infect Langerhans cells of the genitalmucosa underscores the relevance of seminal plasma effects. Virallyinfected cells are eradicated by the killing activity of T cells andnatural killer (NK) cells and this cytotoxicity is stimulated by IL-12(previously known as natural killer cell stimulatory factor) and partlyinhibited by IL-10 (previously known as cytokine synthesis inhibitoryfactor). We have examined the effects of human seminal plasma on theproduction of these key cytokines. Cytokine production was measured inrapidly diluted, fresh, lipopolysaccharide (LPS)-stimulated, whole bloodsince 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%) toblood 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 fiveseparate experiments, from a control value of 1 (no seminal plasma) to amean value of 80 (1% seminal plasma). This cytokine switch was also seenwhen seminal plasma was substituted by pure prostaglandin E (PGE) and 19-OHPGE (the main prostaglandin constituent of human seminal plasma).Lipid-extracted seminal plasma was considerably less active at highdilutions than whole seminal plasma at the same dilution. However, itsactivity could be restored by the addition of synthetic PGE and 19- hydroxyPGE. A stimulation of IL-10 and a decrease in IL-12 in host- defence cellsof the lower female reproductive tract will seriously affect the ability ofcytotoxic T cells and NK cells to recognise and destroy virally infectedcells. In addition, the stimulation of IL-10 will inhibit the release ofthe anti-HIV activity from CD8+ve cells. The cytokine switch reported here,activated by semen deposition, would exercise a key inhibitory control overvital immune defences in the lower genital tract, with ablation ofcell-mediated responses and immunosurveillance.