INHIBITION OF INTERFERON-GAMMA-INDUCED INTERLEUKIN-12 PRODUCTION - A POTENTIAL MECHANISM FOR THE ANTIINFLAMMATORY ACTIVITIES OF TUMOR-NECROSIS-FACTOR

Inflammation is associated with production of cytokines and chemokines that recruit and activate inflammatory cells. Interleukin (IL) 12 pro duced by macrophages in response to various stimuli is a potent induce r of interferon (IFN) gamma production. IFN-gamma, in turn, markedly e nhances IL-12 production. Although the immune response is typically se lf-limiting, the mechanisms involved are unclear. We demonstrate that IFN-gamma inhibits production of chemokines (macrophage inflammatory p roteins MIP-1 alpha and MIP-1 beta). Furthermore, pre-exposure to tumo r necrosis factor (TNF) inhibited IFN-gamma priming for production of high levels of IL-12 by macrophages in vitro. Inhibition of IL-12 by T NF can be mediated by both IL-10-dependent and IL-10-independent mecha nisms. To determine: whether TNF inhibition of IFN-gamma-induced IL-12 production contributed to the resolution of an inflammatory response in vivo, the response of TNF+/+ and TNF-/- mice injected with Coryneba cterium parvum were compared. TNF-/- mice developed a delayed, but vig orous, inflammatory response leading to death, whereas TNF+/+ mice exh ibited a prompt response that resolved. Serum IL-12 levels were elevat ed 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 o f TNF in limiting the extent and duration of inflammatory responses in vivo involves its capacity to regulate macrophage IL-12 production. I FN-gamma inhibition of chemokine production and inhibition of IFN-gamm a-induced IL-12 production by TNF provide potential mechanisms by whic h these cytokines can exert anti-inflammatory/repair function(s).