Suppression of human T-cell mitogenesis by prostaglandin. Existence of a prostaglandin-producing suppressor cell.

Abstract

Prostaglandins (PGs) I of the E series have been shown to inhibit many in vitro measurements of immune function in experimental animals. These include macrophage inhibitory factor production in guinea pigs (1, 2), direct cytolysis in murine lymphocytes (3), hemolytic plaque formation by murine leukocytes (4), and mitogen-induced stimulation of murine lymphocytes (5). In the human, Lomnitzer et al. (6) have shown that PGEI and PGE2 cause reduction in leukocyte inhibitory factor production by phytohemagglutinin(PHA)-stimulated human lymphocytes. Smith et al. (7) demonstrated significant inhibition of [3H]thymidine incorporation into PHA-stimulated human lymphocytes by PGEI, E2, At, and F~. As in the study by Lomnitzer, the final concentration of PGs was relatively high, I0-~-I0-4M. Ferraris and Derubertis have reported (8) that stimulation of 10 ~ human luekocytes with optimal concentrations of PHA produced -10-8M PGE.These data suggest that PGs of the E series might act as endogenous modulators in human immune reactions. PGEI is produced in the mitogen stimulation of human leukocytes, and may in turn inhibit this stimulation. Thus, data are accumulating to support the hypothesis of Bourne et al. (9) that PGs are important regulators of immune function. One troublesome aspect of the studies on human leukocytes is the great disparity between the amount of PGE produced during mitogen stimulation (~10-SM or 5 ng/ml) and the amount required to suppress mitogen stimulation when added to cultures (~10-5M or 5 pg/ml).In the present paper we describe the effects of lower, more physiologic concentrations of PGs on mitogen stimulation of human lymphocytes and lymphocyte subpopulations. We also describe the effect of PG synthetase inhibitors on mitogen-induced stimulation of these cells. We have identified a population of glass adherent mononuclear cells that suppress T-cell mitogenic activity through production of PGs of the E series.

Monocytes regulate osteoclast-activating factor production by releasing prostaglandins.

“…Similar results have been described by Goodwin et al (34). They demonstrated the presence of prostaglandin-producing suppressor ceils which adhered to glass-wool in patients with Hodgkin's disease (34) and normal persons (35). Our leukocytes were obtained from normal human peripheral blood obtained from plateletpheresis donations.…”

Bacterial cell wall-induced immunosuppression. Role of transforming growth factor beta.

“…Initial attempts to define this suppressor molecule involved the addition of inhibitors of several previously defined macrophage suppressor molecules including prostaglandins (19) and reactive oxygen intermediates (20) . Although SCW added directly to spleen cell and/or macrophage cultures induces PGE2 synthesis and 02 generation (Feldman et al ., manuscript in preparation), the addition of indomethacin (10-6 M), superoxide dismutase (up to 600 leg/ml) and/or catalase (up to 10,000 U/ml) to the suppressed spleen cell cultures was ineffective in reversing the diminished mitogenic response (data not shown) .…”

“…Activated macrophages have frequently been associated with various forms of immunodeficiency, and a number of macrophage-derived suppressor molecules have been reported including prostaglandins (19), reactive oxygen intermediates (20), and a variety of uncharacterized factors produced in response to virus, mycobacteria, and other stimuli (29)(30)(31)(32)(33). The peptidoglycan-polysaccharide polymers of SCW stimulate human (Allen et al ., manuscript in preparation) and rat (Feldman et al .…”

Immunological tolerance induced by liver grafting in the rat: splenic macrophages and T cells mediate distinct phases of immunosuppressive activity

“…Of particular importance is the ability of macrophages to act as a source of prostaglandins, which are potent inhibitors of several lymphocyte functions, such as mitogenesis (Goodwin, Bankhurst & Messner, 1977), cytolysis (Lichtensteine; a/., 1972; Koga et al, 1982), lymphokine production (Gordon, Bray & Morlcy, 1976), and proliferation (Stout & Fisher, 1982). The principal inhibitory prostaglandins released by suppressor macrophages appears to be those ofthe E series (PGEi, PGE2) (Humes et al, 1977;Kurland & Bockman, 1978;Stenson & Parker, 1980), the production of which is blocked by indomethacin.…”