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Volume 272, Number 9, Issue of February 28, 1997 pp. 5495-5500
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.

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Selective Activation of cAMP-dependent Protein Kinase Type I Inhibits Rat Natural Killer Cell Cytotoxicity

(Received for publication, August 6, 1996, and in revised form, November 15, 1996)

Knut Martin Torgersen ^§ , John Torgils Vaage , Finn Olav Levy ^§ , Vidar Hansson ^§ , Bent Rolstad and Kjetil Taskén ^§

From the Departments of  Anatomy and ^§ Medical Biochemistry, Institute of Basic Medical Sciences, University of Oslo, N-0317 Oslo, Norway

The present study examines the expression and involvement of cAMP-dependent protein kinase (PKA) isozymes in cAMP-induced inhibition of natural killer (NK) cell-mediated cytotoxicity. Rat interleukin-2-activated NK cells express the PKA -isoforms RI, RII, and C and contain both PKA type I and type II. Prostaglandin E₂, forskolin, and cAMP analogs all inhibit NK cell lysis of major histocompatibility complex class I mismatched allogeneic lymphocytes as well as of standard tumor target cells. Specific involvement of PKA in the cAMP-induced inhibition of NK cell cytotoxicity is demonstrated by the ability of a cAMP antagonist, (R_p)-8-Br-adenosine 3,5-cyclic monophosphorothioate, to reverse the inhibitory effect of complementary cAMP agonist (S_p)-8-Br-adenosine 3,5-cyclic monophosphorothioate. Furthermore, the use of cAMP analog pairs selective for either PKA isozyme (PKA type I or PKA type II), shows a preferential involvement of the PKA type I isozyme, indicating that PKA type I is necessary and sufficient to completely abolish killer activatory signaling leading to NK cell cytotoxicity. Finally, combined treatment with phorbol ester and ionomycin maintains NK cell cytotoxicity and eliminates the cAMP-mediated inhibition, demonstrating that protein kinase C and Ca²⁺-dependent events stimulate the cytolytic activity of NK cells at a site distal to the site of cAMP/PKA action.

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