IL-1 synergy with IL-2 in the generation of lymphokine activated killer cells is mediated by TNF-alpha and beta (lymphotoxin).
Interleukin 1 is a pleuripotent cytokine shown to synergize with IL-2 in the generation of lymphokine-activated killer (LAK) cells, when cultured with human peripheral blood mononuclear cells (PBMC) or peripheral blood lymphocytes (PBL). When IL-1 and low dose IL-2 are added in combination, both LAK cytotoxicity and proliferation are increased in short-term (5-6 day) and long-term (12-14 day) cultures compared with cells activated with IL-2 alone. The purpose of this study was to examine the contribution of tumor necrosis factor (TNF-alpha), lymphotoxin (LT, or TNF-beta) and the TNF receptor in the observed IL-1/IL-2 mediated synergy. Analysis of lymphocyte culture supernatants using the L929 bioassay and by specific ELISAs demonstrated an increased production of both TNF and LT in those cells cultured with IL-1 and IL-2. Utilizing specific neutralizing antisera, our experiments demonstrated the biologic activity of both cytokines, with LT-specific antibodies producing the greatest diminution of IL-1/IL-2 stimulated cell proliferation and cytotoxicity. The addition of IL-1 and IL-2 in combination markedly upregulated TNF-receptor expression (measured by Scatchard analysis) in comparison with cells stimulated with IL-2 alone. Characterization of the TNF-R by flow cytometric analysis revealed increased membrane expression of the 75 kDa, but not the 55 kDa, TNF binding protein as a result of IL-1 costimulation.
Lazenby
A W
AW
Department of Thoracic Surgery, University of Texas, M.D. Anderson Cancer Center, Houston 77030.
Roth
J A
JA
Owen-Schaub
L B
LB
Grimm
E A
EA
D000911:Antibodies, Monoclonal; D003602:Cytotoxicity, Immunologic; D004357:Drug Synergism; D006801:Humans; D066298:In Vitro Techniques; D007375:Interleukin-1 / Q000008:administration & dosage*; D007376:Interleukin-2 / Q000008:administration & dosage*; D015979:Killer Cells, Lymphokine-Activated / Q000276:immunology*; D008213:Lymphocyte Activation; D008233:Lymphotoxin-alpha / Q000276:immunology / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000276:immunology; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism
D000911:Antibodies, Monoclonal; D007375:Interleukin-1; D007376:Interleukin-2; D008233:Lymphotoxin-alpha; D011956:Receptors, Cell Surface; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha