Anti-tumor necrosis factor modulates anti-CD3-triggered T cell cytokine gene expression in vivo

J Clin Invest. 1994 May;93(5):2189-96. doi: 10.1172/JCI117215.

Abstract

De novo expression of TNF, IFN gamma, IL-3, IL-4, and IL-6 genes was initiated rapidly by treatment of mice with anti-CD3. A specific feature of this reaction was that TNF was derived exclusively from T cells. TNF was produced both as a mature soluble trimeric protein and as a 26-kD anti-TNF-reactive protein compatible with membrane-anchored TNF. Pretreatment with anti-TNF did not affect anti-CD3-triggered TNF mRNA expression in T cells. In contrast, in vivo and in vitro anti-TNF treatment upregulated anti-CD3-induced IFN gamma mRNA expression and inhibited IL-4 mRNA expression. These latter effects were not dependent on TNF neutralization: pretreatment with soluble recombinant 55-kD TNF receptor (TBPI) as an alternative TNF-neutralizing agent did not modify the anti-CD3-induced cytokine profile. These results suggest that a direct interaction between anti-TNF and T cell membrane-anchored TNF could account for the observed modulation of cytokine gene expression. The increased expression of INF gamma mRNA observed in anti-TNF-treated animals correlated with a decrease in IL-3 and IL-6 mRNA expression. Conversely, IFN gamma blockade by a neutralizing anti-IFN gamma mAb led to a substantial increase in both IL-3 and IL-6 gene expression induced by anti-CD3. Taken together, these results strongly argue for the existence, in the anti-CD3-induced cytokine cascade, of IFN gamma-dependent regulation of IL-3 production, which in turn modulates IL-6 production.

MeSH terms

  • Animals
  • Antibodies, Monoclonal / pharmacology
  • CD3 Complex / drug effects
  • CD3 Complex / immunology
  • CD3 Complex / metabolism*
  • Cytokines / biosynthesis*
  • Gene Expression
  • Immunosuppression
  • Interferon-gamma / immunology
  • Interferon-gamma / metabolism
  • Lymphocyte Activation*
  • Mice
  • Mice, Inbred BALB C
  • RNA, Messenger / biosynthesis
  • Signal Transduction
  • Spleen / cytology
  • Spleen / metabolism
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / metabolism*
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / immunology
  • Tumor Necrosis Factor-alpha / metabolism*

Substances

  • Antibodies, Monoclonal
  • CD3 Complex
  • Cytokines
  • RNA, Messenger
  • Tumor Necrosis Factor-alpha
  • Interferon-gamma