Synergistic proliferation and activation of natural killer cells by interleukin 12 and interleukin 18.
We investigated the effects of IL-12 and IL-18 on unstimulated murine splenocytes and observed that the two cytokines strongly synergized for their proliferation, whereas IL-12 and IL-18 alone were essentially inactive in this respect. Phenotypical and functional analyses of cells proliferating in response to IL-12 and IL-18 revealed that large granular Ly-49C(+)DX5(+)CD3(-)NK blasts were expanded in these cultures and that they displayed cytotoxic activity against Yac-1 cells, a murine NK cell target. Further analyses indicated three major differences between NK cells appearing in response to IL-12 and IL-18 and those derived in the presence of other NK cell growth factors, such as IL-2 or IL-15. First, a population of T-NK cells, i.e. expressing T cell (TCRalphabeta, CD3) and NK cell (Ly-49) markers, was detected amongst cells growing in IL-2 or IL-15 but not in cultures supplemented with IL-12 and IL-18. Second, most NK cells derived with IL-2 or IL-15 expressed the NK1.1 antigen, while those derived with IL-12 and IL-18 did not. Finally, striking differences were observed regarding cytokine production. Cells stimulated with IL-12 and IL-18 in combination, but not with IL-2 or IL-15, produced IFN-gamma, IL-3, IL-6 and TNF. IFN-gamma was not involved in the response of NK cells to IL-12 and IL-18, as indicated by experiments demonstrating that the combination of the two cytokines displayed similar effects on spleen cells from IFN-gammaR-knock-out mice. Receptor (IL-12Rbeta1, IL-12Rbeta2 and IL-18R) gene expression studies did not indicate that the mechanism underlying the synergy between IL-12 and IL-18 involved reciprocal induction of their receptors. Taken together, our results demonstrate that IL-12 and IL-18 exert striking synergistic activities for NK cell proliferation and activation, distinct from those induced by IL-2 or IL-15.
Lauwerys
B R
BR
Christian de Duve Institute of Cellular Pathology, Université catholique de Louvain, Bruxelles, Belgium.
Renauld
J C
JC
Houssiau
F A
FA
D000818:Animals; D000954:Antigens, Surface / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis; D004357:Drug Synergism; D005434:Flow Cytometry; D015870:Gene Expression / Q000187:drug effects; D016130:Immunophenotyping; D007371:Interferon-gamma / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology / Q000502:physiology; D018664:Interleukin-12 / Q000235:genetics / Q000494:pharmacology*; D019409:Interleukin-15 / Q000494:pharmacology; D020382:Interleukin-18 / Q000235:genetics / Q000494:pharmacology*; D053727:Interleukin-18 Receptor alpha Subunit; D007376:Interleukin-2 / Q000494:pharmacology; D007694:Killer Cells, Natural / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D018345:Mice, Knockout; D018123:Receptors, Interleukin / Q000096:biosynthesis / Q000235:genetics; D053707:Receptors, Interleukin-12; D053724:Receptors, Interleukin-18; D013154:Spleen / Q000166:cytology / Q000187:drug effects
D000954:Antigens, Surface; D016207:Cytokines; C508573:Il18r1 protein, mouse; D019409:Interleukin-15; D020382:Interleukin-18; D053727:Interleukin-18 Receptor alpha Subunit; D007376:Interleukin-2; D018123:Receptors, Interleukin; D053707:Receptors, Interleukin-12; D053724:Receptors, Interleukin-18; D018664:Interleukin-12; D007371:Interferon-gamma