CELLULAR IMMUNOLOGY 106,43-52 (1987) Effect of in Vivo Administration of Prostaglandins and Interferon on Natural Killer Activity and on B-l 6 Melanoma Growth in Mice’ ENRICO GARACI, ANTONIO MASTINO, TERESA JEZZI, CARLO RICCARDI, AND CARTESIO FAVALLI* Department of Experimental Medicine, II University of Rome, 00173 Rome, Italy, and Institute of Pharmacology, University ofPerugia, 06100 Perugia, Italy Received August 12, 1986; acceptedDecember 5, 1986 We investigated the effect on in vivo administrationof 16,16dimethyl-prostaglandin E2 (di- M-PGE2) alone and in combinedtreatmentwith a-p interferon (IPN) on (a) NK activity in normal, cyclophosphamide (CY)-treated, tumor bearing or irradiatedandbonemarrowmcon- stitutedmiceand (b) on B-16melanoma growth.Normal miceinoculated with IFN (30,000 U/ mouse, 24 hr before testing)showed a significantincrease in NK activity, while thosetreated with di-M-PGE2 (IO &mouse daily X 4 days) showed a suppressed NK response. No difference wasobserved between mice treated with di-M-PGE2 aloneand those treated with di-M-PGEZ associated with IPN. In immunosuppressed animals single treatments were slightly (di-M-PGE*) or not (IPN) effective, while the combinedadministration of di-M-PGE2and IPN caused a marked increase in NK activity. Moreover,di-M-F’GE2 wasableto accelerate the recovery rate of NK activity in bone marrow-reconstituted murine chimeras, suggesting that the synergistic effect of prostaglandins and IPN could derivefrom the action of di-M-PGE2 on progenitor pre- NK cellsand of IPN on effector cells.Finally, we observed a goodcorrelationbetween the en- hancement of the NK activity andthe tumor growthinhibition. 8 1987 Academic press, IIIC. INTRODUCTION Prostaglandins (PGs)~ are implicated in the control of immune response and in particular in natural killer (NK) activity (l-7). In vitro studies suggest that prostaglan- dins of the E series (PGE) can exert a negative control in murine (8) and in human (9) NK activity, but much less is known about their in vivo action on NK cells in normal or in immunosuppressed animals. Our recent studies have showed a dichotomy in the action of l&16-dimethyl-pros- taglandin E2 (di-M-PGE2), a long-acting synthetic analog of PGE2 on the immune system, showing that PGs are involved in the control of in vivo tumor growth largely by virtue of their effectson the modulation of immune response( 10).The mechanism ’ Supported by grantsof the Italian National Research Council, Special Project“Oncology” Contract 85.02150.44, and Special Project “Infectious Diseases” Contract8500852.52. ’ To whomrequests for reprintsshould beaddressed at the II University of Rome, Department of Experi- mentalMedicine,Via OrazioRaimondo, 00173 Rome, Italy. ’ Abbreviations used PC&, prostaglandins; NK, natural killer, di-M-PGE2 , 16- 16dimethyl-prostaglan- din El; IFN, interferon;CY, cyclophosphamide; PBS, phosphate-buffered saline; HBSS, Hanks’balanced saltsolution; L&e, lytic unihO; BRM, biologicalresponse modifier. 43 0008-8749187 $3.00 Copyright Q 1987 by Academic Press, Inc. All rights of reproduction in any form reserved.