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

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 macrophagesin 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 responsein vivo, the response of TNF+/+and TNF−/−mice injected withCorynebacterium parvumwere 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 inC. parvum-treated TNF−/−mice compared with TNF+/+mice. Treatment with a neutralizing anti-IL-12 antibody led to resolution of the response toC. parvumin TNF−/−mice. We conclude that the role of TNF in limiting the extent and duration of inflammatory responsesin vivoinvolves 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).