HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 ENVELOPE PROTEIN DOES NOT STIMULATE EITHER PROSTAGLANDIN FORMATION OR THE EXPRESSION OF PROSTAGLANDIN-HSYNTHASE IN THP-1 HUMAN MONOCYTES MACROPHAGES

Prostaglandin E(2) is observed at elevated levels during human immunod eficiency virus (HIV) infection and thus may contribute to the HIV-dep endent immunosuppression. The mechanisms responsible for this increase are not understood. Evidence indicates that the viral envelope protei ns perturb membrane signaling mediated by the CD4 receptor, suggesting that the free envelope protein and/or the intact virus may be respons ible for the increase in prostaglandin E(2) levers. In this study, we have used THP-1 human monocytes and THP-1 cells differentiated by 12-O -tetradecanoylphorbol-13-acetate treatment into macrophages to determi ne if the HIV envelope protein, gp120, or an anti-CD4 receptor antibod y stimulates prostaglandin formation by interacting with the CD4 recep tor. Incubation of THP-1 cells with OKT4A antibody greatly stimulated the CD4-p56(lck): receptor complex as estimated by enhanced p56(lck) a utophosphorylation, whit the gp120 gave small but significant response s. Monocytic THP-1 cells poorly metabolized arachidonic acid to prosta glandin E(2) and thromboxane B-2 as measured by high-pressure liquid c hromatography analysis. Western blot (immunoblot) and Northern (RNA) b lot analyses revealed that unstimulated monocytes expressed little pro staglandin H synthase 1 and 2 (PGHS-1 and -2). Incubation of the monoc ytes with lipopolysaccharide, OKT4A, or gp120 did not increase the for mation of prostaglandins. The expression of PGHS-1 or PGHS-2 was also not increased. Differentiation of the monocytes to macrophages by 12-O -tetradecanoylphorbol-13-acetate treatment resulted in increased expre ssion of PGHS-1 and increased formation of prostaglandins compared wit h that for the monocytes. Lipopolysaccharide stimulation of the macrop hages increased the formation of prostaglandins and increased the expr ession of PGHS-2 in the macrophages. However, OKT4A or gp120 preparati on, at concentrations that stimulated p56(lck) autophosphorylation, di d not enhance the formation of prostaglandins or the expression of PGH S-1 or PGHS-2. OKT4A and gp120 also did not stimulate the release of a rachidonic acid, indicating that phospholipase A(2) was not activated by the CD4 receptor in either the THP-I monocytes or macrophages. Thes e results indicate that activation of the CD4-p56(lck) receptor signal transduction pathway by the HIV envelope protein does not increase pr ostaglandin formation.