Transforming growth factor-beta 1 (TGF-beta 1) and recombinant human tumor necrosis factor-alpha reciprocally regulate the generation of lymphokine-activated killer cell activity. Comparison between natural porcine platelet-derived TGF-beta 1 and TGF-beta 2, and recombinant human TGF-beta 1.
We have investigated the ability of porcine-platelet-derived transforming growth factor-beta 1 (TGF-beta 1) to inhibit the generation of lymphokine-activated killer (LAK) cells by human rIL-2. The results demonstrate that TGF-beta 1, in a dose-related manner, significantly inhibits rIL-2-induced LAK cell activity against Daudi and COLO target cells and, to a lesser degree, against K-562 cells. Maximal inhibition was obtained by the addition of TGF-beta 1 at the time of culture initiation and, to a lesser degree, on day 1. Only minimal inhibition was obtained when TGF-beta 1 addition was delayed until day 2 of culture or when added directly into the LAK cell assay. Additional studies demonstrated that porcine platelet-derived TGF-beta 2 and human rTGF-beta 1 inhibited LAK cell generation similar to that obtained with TGF-beta 1. The inhibition of LAK cell activity by TGF-beta 1 was reversed by the addition of human rTNF-alpha at the initiation of culture. In addition, rTNF-alpha synergized with suboptimal levels of rIL-2 in the generation of LAK activity. After stimulation with rIL-2, LAK cells produced significant levels of IFN-gamma, TNF-alpha, and TNF-beta. TGF-beta 1 inhibited the production of these cytokines in a dose-related manner. The results extend the previous known activities for human rTNF-alpha and TGF-beta 1 and further demonstrate the reciprocal relationship between these two molecules in the regulation of certain immune functions.
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Department of Molecular Biology and Immunology, Genentech, Inc., South San Francisco, CA 94080.
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D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D001688:Biological Products / Q000096:biosynthesis; D001792:Blood Platelets; D016207:Cytokines; D003602:Cytotoxicity, Immunologic / Q000187:drug effects*; D004357:Drug Synergism; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007376:Interleukin-2 / Q000494:pharmacology*; D007694:Killer Cells, Natural / Q000276:immunology*; D008213:Lymphocyte Activation / Q000187:drug effects*; D010455:Peptides / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000494:pharmacology; D013552:Swine; D015291:Transforming Growth Factors; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D000276:Adjuvants, Immunologic; D001688:Biological Products; D016207:Cytokines; D007166:Immunosuppressive Agents; D007376:Interleukin-2; D010455:Peptides; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D015291:Transforming Growth Factors