TGF-beta inhibits the in vitro induction of lymphokine-activated killing activity.
Employing serum-free media, human peripheral blood mononuclear cells, and purified recombinant interleukin-2 (IL-2), conditions were observed in which the development of IL-2-driven cytotoxic activity was suppressed. The cytotoxic activity of such IL-2-generated lymphokine activated killing (LAK) was tested against natural killer-resistant cultured tumor cells (Daudi, Raji, and a glioma). LAK generation was inhibited by addition of some normal sera, normal platelets, or some tumor cells. Because recent reports have indicated that transforming growth factor-beta (TGF-beta)-like factors are often secreted by tumors and the acidic alpha granules of platelets and can be present in sera, we tested the effect of purified human TGF-beta on the activation of LAK. Our results indicated that TGF-beta is very suppressive for LAK induction, and can completely prevent both the IL-2-driven proliferation and cytotoxicity at concentrations as low as 5 ng/ml. Titrations of IL-2 and of TGF-beta indicated that the suppression is dose-dependent and can be avoided by employing higher levels of IL-2. It was also found that the suppressive effect of TGF-beta can be overcome by washing suppressed cell populations and further culture in low levels of IL-2. Collectively, these data indicate that TGF-beta can be a potent inhibitor of LAK generation under standard activation conditions, but that this effect is regulated by the relative level of IL-2 and may be overcome and/or reversed in vitro.
Grimm
E A
EA
Department of Tumor Biology, M.D. Anderson Hospital, Houston, Texas 77030.
Crump
W L
WL
Durett
A
A
Hester
J P
JP
Lagoo-Deenadalayan
S
S
Owen-Schaub
L B
LB
D001792:Blood Platelets / Q000276:immunology; D003470:Culture Media; D003602:Cytotoxicity, Immunologic / Q000187:drug effects*; D004306:Dose-Response Relationship, Immunologic; D006023:Glycoproteins / Q000097:blood; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007376:Interleukin-2 / Q000494:pharmacology; D007694:Killer Cells, Natural / Q000276:immunology*; D008213:Lymphocyte Activation / Q000187:drug effects*; D008222:Lymphokines; D009363:Neoplasm Proteins; D010455:Peptides / Q000494:pharmacology*; D010978:Platelet Factor 4 / Q000494:pharmacology; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D015291:Transforming Growth Factors; D014407:Tumor Cells, Cultured / Q000276:immunology
D003470:Culture Media; D006023:Glycoproteins; D007166:Immunosuppressive Agents; D007376:Interleukin-2; D008222:Lymphokines; D009363:Neoplasm Proteins; D010455:Peptides; D010982:Platelet-Derived Growth Factor; C038588:serum immunosuppressive factor, human; D010978:Platelet Factor 4; D015291:Transforming Growth Factors