Effects of prostaglandins on the development of cell-mediated immunity in culture and on the cytolytic activity of in vivo-generated effector cells

Abstract

This study was undertaken in an attempt to better understand the rôle of prostaglandins in the development of the primary cell-mediated immunity (CMI) response in culture. Primary sensitization cultures with C57Bl/6 mouse spleen cells as responder cells (R) and X-irradiated P815 mastocytoma cells as allogeneic stimulator cells (S) were established in the presence and absence of test agents. The ability of effector cells to lyse P815 target cells was measured by 51Cr-release assay on day 4. 3H-Thymidine uptake into the cultured cells was also analyzed on the same day. Prostaglandins of the E series were shown to exert selective effects on the CMI response depending on dose, schedule of administration, and culture conditions. PGE1 or PGE2 enhanced the CMI response at 30 pM but inhibited it by 50% at 30 nM. At an optimal R/S ratio, 30 nM PGE1, or PGE2 always inhibited 3H-thymidine uptake more than cytotoxicity while at suboptimal ratios it inhibited both equally. PGE1 did not affect the kinetics of development of the CMI responses. PGE1 was inhibitory when added 20 h before, at the same time as or as late as 24 h after antigen. The inhibitory effect was prevented by removal of PGE1 within 24 h of addition. Pretreatment of spleen cells with PGE1 for 20 h did not affect their subsequent response to sensitization. It seems that PGE1 must be present during the early phase of lymphocyte activation and that it has a relatively long half-life in spleen cell cultures. The development of secondary CMI in culture was less sensitive to inhibition by PGE than that of the primary CMI. PGD2 and PGA2 also inhibited the induction of the primary CMI while PGF2 alpha enhanced it. On the other hand, PGI2 and TXB2 had no effect. The effect of prostaglandins on the lytic activity of the in vivo-generated effector cells was also examined. The addition of PGE2, PGI2, PGD2 or PGA2 to the 51Cr-release assay resulted in significant depression of the cell-mediated lympholysis; whereas, addition of 6-keto-PGF1 alpha, TXB2, and PGF2 alpha caused little effect. PGE2, PGA2 or PGD2 inhibited the rate of lytic activity. In order to exert this effect, these compounds must be present during the 51Cr-release assay and pretreatment of the effector cells had little effect on their cytotoxicity. These results indicate that prostaglandins have immunomodulating activity affecting the early phase of the development of the CMI response in culture; they also have the ability to inhibit the cytolytic effect of effector cells generated in vivo.