Upregulation of interferon-γ binding by tumor necrosis factor and lymphotoxin

Disparate potencies of the cytokines and modulation of their effects by phorbol ester

A. B. Raitano, P. Scuderi, Murray Korc

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

Tumor necrosis factor (TNF) and interferon-γ (IFN-γ) are immune- modulating cytokines that exert synergistic cytotoxic effects in several types of tumor cells, including ASPC-1 human pancreatic carcinoma cells. Lymphotoxin (LT), is a cytokine that binds to the TNF receptor and mimicks most of the biological actions of TNF. In the present study, we examined ASPC-1 cells for cytokine-mediated modulation of TNF and IFN-γ receptors. Treatment of ASPC-1 cells with recombinant human IFN-γ (rhIFN-γ) did not significantly alter 125I-rhTNF binding. In contrast, treatment with rhTNF led to a dose- and time-dependent increase in 125I-rhIFN-γ binding and internalization. Scatchard analysis revealed that rhTNF increased the number of 125I-rhIFN-γ binding sites from 11,000 sites/cell to 23,000 sites/cell without altering receptor affinity. Although rhLT also increased 125I- rhIFN-γ binding, it was 100-fold less potent than rhTNF. In contrast, rhLT was only 10-fold less potent than rhTNF in displacing 125I-rhTNF from its receptor. The phorbol ester 12-O-tetradecanoyl phorbol-13-acetate (TPA) blocked the rhLT- and rhTNF-mediated increase in 125I-rhIFN-γ binding and markedly decreased 125I-rhTNF binding. These data suggest that both TNF and LT upregulate IFN-γ receptors in ASPC-1 cells, but that LT is much less efficient than TNF. Further, the TPA-induced attenuation of IFN-γ receptor upregulation suggests that protein kinase C activation can regulate the TNF/LT-mediated pathways involved in IFN-γ receptor upregulation.

Original languageEnglish (US)
Pages (from-to)61-67
Number of pages7
JournalJournal of Interferon Research
Volume11
Issue number1
StatePublished - 1991
Externally publishedYes

Fingerprint

Lymphotoxin-alpha
Phorbol Esters
Interferons
Interferon Receptors
Up-Regulation
Tumor Necrosis Factor-alpha
Cytokines
Tumor Necrosis Factor Receptors
Tetradecanoylphorbol Acetate
Protein Kinase C
Interferon-gamma
Binding Sites

ASJC Scopus subject areas

  • Immunology
  • Virology

Cite this

Upregulation of interferon-γ binding by tumor necrosis factor and lymphotoxin : Disparate potencies of the cytokines and modulation of their effects by phorbol ester. / Raitano, A. B.; Scuderi, P.; Korc, Murray.

In: Journal of Interferon Research, Vol. 11, No. 1, 1991, p. 61-67.

Research output: Contribution to journalArticle

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abstract = "Tumor necrosis factor (TNF) and interferon-γ (IFN-γ) are immune- modulating cytokines that exert synergistic cytotoxic effects in several types of tumor cells, including ASPC-1 human pancreatic carcinoma cells. Lymphotoxin (LT), is a cytokine that binds to the TNF receptor and mimicks most of the biological actions of TNF. In the present study, we examined ASPC-1 cells for cytokine-mediated modulation of TNF and IFN-γ receptors. Treatment of ASPC-1 cells with recombinant human IFN-γ (rhIFN-γ) did not significantly alter 125I-rhTNF binding. In contrast, treatment with rhTNF led to a dose- and time-dependent increase in 125I-rhIFN-γ binding and internalization. Scatchard analysis revealed that rhTNF increased the number of 125I-rhIFN-γ binding sites from 11,000 sites/cell to 23,000 sites/cell without altering receptor affinity. Although rhLT also increased 125I- rhIFN-γ binding, it was 100-fold less potent than rhTNF. In contrast, rhLT was only 10-fold less potent than rhTNF in displacing 125I-rhTNF from its receptor. The phorbol ester 12-O-tetradecanoyl phorbol-13-acetate (TPA) blocked the rhLT- and rhTNF-mediated increase in 125I-rhIFN-γ binding and markedly decreased 125I-rhTNF binding. These data suggest that both TNF and LT upregulate IFN-γ receptors in ASPC-1 cells, but that LT is much less efficient than TNF. Further, the TPA-induced attenuation of IFN-γ receptor upregulation suggests that protein kinase C activation can regulate the TNF/LT-mediated pathways involved in IFN-γ receptor upregulation.",
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