Cytokine regulation of tumor necrosis factor-alpha and -beta (lymphotoxin)-messenger RNA expression in human peripheral blood mononuclear cells

The immune response at the molecular level is characterized by a carefully coordinated interplay of both cytokine production and receptor induction. The regulation of these molecules including the closely related tumor necrosis factors alpha (TNF) and beta (lymphotoxin, LT) is still incompletely und...

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Published in:Cancer research (Chicago, Ill.) Ill.), 1990-08, Vol.50 (16), p.5072-5076
Main Authors: Kasid, A, Director, E P, Stovroff, M C, Lotze, M T, Rosenberg, S A
Format: Article
Language:English
Subjects:
Actins - genetics
Biological Factors - pharmacology
Cells, Cultured
Colony-Stimulating Factors - pharmacology
Cytokines
Gene Expression Regulation - drug effects
Granulocyte-Macrophage Colony-Stimulating Factor
Growth Substances - pharmacology
Humans
Interleukins - pharmacology
Leukocytes, Mononuclear - drug effects
Leukocytes, Mononuclear - physiology
Lymphotoxin-alpha - blood
Lymphotoxin-alpha - genetics
Plasmids
Recombinant Proteins - pharmacology
RNA - blood
RNA - genetics
RNA - isolation & purification
RNA, Messenger - drug effects
RNA, Messenger - genetics
Tumor Necrosis Factor-alpha - genetics
Tumor Necrosis Factor-alpha - metabolism
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Summary:The immune response at the molecular level is characterized by a carefully coordinated interplay of both cytokine production and receptor induction. The regulation of these molecules including the closely related tumor necrosis factors alpha (TNF) and beta (lymphotoxin, LT) is still incompletely understood. We have examined the effects of various cytokines on the expression of TNF and LT mRNA in human peripheral blood mononuclear cells (PBMC). Northern blot analysis with total cellular RNA from mixed populations of PBMC revealed that genes coding for TNF and LT were not spontaneously expressed. Treatment of PBMC with recombinant interleukin (IL)-2 resulted in a high level expression of TNF and LT mRNA. Whereas IL-1 beta was equally effective as IL-2 in inducing both TNF and LT mRNA, granulocyte-macrophage colony-stimulating factor selectively induced only TNF mRNA. Both TNF and LT mRNA were minimally induced by IL-1 alpha, IL-3, interferon (IFN)-alpha, or IFN-gamma. Similarly TNF alone had little effect on induction of TNF and LT mRNA. In conjunction with IL-2, cytokines such as IFN-alpha, IFN-gamma, or TNF did not interfere with IL-2 induction of TNF and LT mRNA. Interestingly, IL-4 in combination with IL-2 inhibited the IL-2-driven induction of TNF and LT mRNA. This inhibitory effect of IL-4 was also observed at the level of TNF and LT protein secretion. Furthermore, IL-4 was also inhibitory of IL-2-mediated induction of Tac mRNA in PBMC. These results extend the interrelationship of cytokine regulation of TNF and LT expression. In particular, they reveal the previously unrecognized function of IL-4 in antagonizing the IL-2 induction of TNF, LT, and Tac mRNA in PBMC.
ISSN:0008-5472