Regulation of lymphokine-activated killer cell induction by human recombinant IL-1 receptor antagonist. Obligate paracrine pathway of IL-1 during lymphokine-activated killer cell induction.
IL-2-stimulated human lymphocytes, referred to as lymphokine-activated killer (LAK) cells, can develop a broad range of lytic activity against fresh tumor cells and cultured tumor cell lines. IL-1, a pleiotropic cytokine shown to synergize with IL-2 on LAK induction, is endogenously synthesized and secreted by LAK cells. Immunoblot analysis demonstrated that IL-2-stimulated PBL produced the 31- to 34-kDa pro-molecules of IL-1 within 24 h and maintained their expression for at least 96 h. The role of secreted IL-1 has been examined using rIL-1R antagonist (IL-1ra). The addition of IL-1ra to LAK activation culture resulted in dose-dependent inhibited lytic activity, which was more apparent in LAK cells cultured with higher doses of IL-2. However, IL-1ra had no effect on proliferative responses elicited in LAK cells by IL-2. Moreover, when IL-1 binding was blocked by IL-1ra, the expression of the IL-2R p55 subunit was reduced compared with control LAK cells. The effect of IL-1 binding blockade on expression of other cytokine mRNA was further examined by polymerase chain reaction analysis, and, specifically, inhibition of both TNF-alpha and TNF-beta mRNA expression by IL-1ra was observed in PBL stimulated with IL-2. The reduced biologic activity of TNF in culture supernatants correlated well with the inhibition of mRNA expression. These findings suggest that autocrine/paracrine IL-1 is involved in the initial generation of LAK activity and, in particular, that TNF expression could be induced via an IL-1 autocrine pathway.
Fujiwara
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Department of Tumor Biology, The University of Texas M. D. Anderson Cancer Center, Houston 77030.
Grimm
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EA
D001483:Base Sequence; D015152:Blotting, Northern; D003602:Cytotoxicity, Immunologic / Q000502:physiology*; D004306:Dose-Response Relationship, Immunologic; D007375:Interleukin-1 / Q000502:physiology*; D007376:Interleukin-2 / Q000032:analysis; D015979:Killer Cells, Lymphokine-Activated / Q000502:physiology*; D008233:Lymphotoxin-alpha / Q000032:analysis; D008969:Molecular Sequence Data; D016133:Polymerase Chain Reaction; D012313:RNA / Q000032:analysis; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors; D017472:Receptors, Interleukin-1; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
D007375:Interleukin-1; D007376:Interleukin-2; D008233:Lymphotoxin-alpha; D011971:Receptors, Immunologic; D017472:Receptors, Interleukin-1; D014409:Tumor Necrosis Factor-alpha; D012313:RNA