Inhibition of interferon γ induced interleukin 12 production: A potential mechanism for the anti-inflammatory activities of tumor necrosis factor

Jennifer Hodge-Dufour, Michael W. Marino, Maureen R. Horton, Achim Jungbluth, Marie D. Burdick, Robert M. Strieter, Paul W. Noble, Christopher A. Hunter, Ellen Puré

Research output: Contribution to journalArticlepeer-review

Abstract

Inflammation is associated with production of cytokines and chemokines that recruit and activate inflammatory cells. Interleukin (IL) 12 produced by macrophages in response to various stimuli is a potent inducer of interferon (IFN) γ production. IFN-γ, in turn, markedly enhances IL-12 production. Although the immune response is typically self-limiting, the mechanisms involved are unclear. We demonstrate that IFN-γ inhibits production of chemokines (macrophage inflammatory proteins MIP-1α and MIP-1β). Furthermore, pre-exposure to tumor necrosis factor (TNF) inhibited IFN-γ priming for production of high levels of IL-12 by macrophages in vitro. Inhibition of IL-12 by TNF can be mediated by both IL-10-dependent and IL- 10-independent mechanisms. To determine whether TNF inhibition of IFN-γ- induced IL-12 production contributed to the resolution of an inflammatory response in vivo, the response of TNF(+/+) and TNF(-/-) mice injected with Corynebacterium parvum were compared. TNF(-/-) mice developed a delayed, but vigorous, inflammatory response leading to death, whereas TNF(+/+) mice exhibited a prompt response that resolved. Serum IL-12 levels were elevated 3-fold in C. parvum-treated TNF(-/-) mice compared with TNF(+/+) mice. Treatment with a neutralizing anti-IL-12 antibody led to resolution of the response to C. parvum in TNF(-/-) mice. We conclude that the role of TNF in limiting the extent and duration of inflammatory responses in vivo involves its capacity to regulate macrophage IL-12 production. IFN-γ inhibition of chemokine production and inhibition of IFN-γ-induced IL-12 production by TNF provide potential mechanisms by which these cytokines can exert anti- inflammatory/repair function(s).

Original languageEnglish (US)
Pages (from-to)13806-13811
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume95
Issue number23
DOIs
StatePublished - Nov 10 1998

ASJC Scopus subject areas

  • General

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