Functional consequences of cAMP accumulation in human natural killer cells. Implications for IL-2 and IL-4 signal transduction.
To approach the mechanisms whereby IL-2 activates human NK cells, we have compared the effects of IL-4 and of Bt2cAMP on this activation. Both agents block completely the proliferation induced by IL-2 on highly purified CD3-negative human NK cells. We also report that the net LAK response of PBL is inhibited by IL-4 and cAMP. However, kinetics analysis showed that IL-4 appears to inhibit an early stage of IL-2-induced activation of NK cells. IL-4 does not affect the cytotoxicity of freshly isolated NK cells against the K562 target and is ineffective on IL-2-preactivated cells. In contrast, cAMP primarily blocks the lytic effector phase, whether cells have been cultured in IL-2 or not, and its effect appears independent of time of addition. These differences between the activity of IL-4 and cAMP suggested that cAMP was not directly involved in IL-4 signal transduction in human NK cells. Consistent with this interpretation, we did not observe any variation in the level of intracellular cAMP concentrations when NK cells were stimulated with IL-4, or when they are stimulated with IL-2 or IL-2 plus IL-4. In addition, we also demonstrate that NK cell cytotoxic activation induced by IL-2 is still demonstrable in the presence of Bt2cAMP under conditions in which NK cell proliferation is blocked. These results clearly indicate that the differentiative effect of IL-2 on NK cells is independent of cell proliferation. Furthermore, the p70-75 IL-2R-initiated signal transduction pathway that leads to increased cytotoxicity appears not to be susceptible to inhibition by cAMP in human NK cells.
Vitté-Mony
I
I
Institut National de la Santé et de la Recherche Médicale, Unité 333, Institut Gustave Roussy, Villejuif, France.
Stancou
R
R
Bertoglio
J H
JH
D000945:Antigens, Differentiation, T-Lymphocyte / Q000032:analysis; D003994:Bucladesine / Q000494:pharmacology; D017252:CD3 Complex; D002454:Cell Differentiation / Q000187:drug effects; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism*; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D006801:Humans; D007376:Interleukin-2 / Q000502:physiology*; D015847:Interleukin-4 / Q000502:physiology*; D015979:Killer Cells, Lymphokine-Activated / Q000276:immunology; D007694:Killer Cells, Natural / Q000502:physiology*; D007700:Kinetics; D008213:Lymphocyte Activation / Q000187:drug effects; D011948:Receptors, Antigen, T-Cell / Q000032:analysis
D000945:Antigens, Differentiation, T-Lymphocyte; D017252:CD3 Complex; D007376:Interleukin-2; D011948:Receptors, Antigen, T-Cell; D005576:Colforsin; D015847:Interleukin-4; D003994:Bucladesine; D000242:Cyclic AMP