title: Inhibition of interferon gamma induced interleukin 12 production: a potential mechanism for the anti-inflammatory activities of tumor necrosis factor.
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) gamma production. IFN-gamma, in turn, markedly enhances IL-12 production. Although the immune response is typically self-limiting, the mechanisms involved are unclear. We demonstrate that IFN-gamma inhibits production of chemokines (macrophage inflammatory proteins MIP-1alpha and MIP-1beta). Furthermore, pre-exposure to tumor necrosis factor (TNF) inhibited IFN-gamma 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-gamma-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-gamma inhibition of chemokine production and inhibition of IFN-gamma-induced IL-12 production by TNF provide potential mechanisms by which these cytokines can exert anti-inflammatory/repair function(s).
authors.affiliation: Immunology Graduate Group, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: J
authors.initials: J
authors.lastname: Hodge-Dufour
authors.forename: M W
authors.initials: MW
authors.lastname: Marino
authors.forename: M R
authors.initials: MR
authors.lastname: Horton
authors.forename: A
authors.initials: A
authors.lastname: Jungbluth
authors.forename: M D
authors.initials: MD
authors.lastname: Burdick
authors.forename: R M
authors.initials: RM
authors.lastname: Strieter
authors.forename: P W
authors.initials: PW
authors.lastname: Noble
authors.forename: C A
authors.initials: CA
authors.lastname: Hunter
authors.forename: E
authors.initials: E
authors.lastname: Puré
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D004336:Drug Antagonism; D005260:Female; D007249:Inflammation / Q000517:prevention & control; D007371:Interferon-gamma / Q000494:pharmacology*; D018664:Interleukin-12 / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D019402:Macrophage Inflammatory Proteins / Q000096:biosynthesis; D017737:Macrophages, Peritoneal / Q000276:immunology*; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
chemical_list: D000893:Anti-Inflammatory Agents; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D019402:Macrophage Inflammatory Proteins; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12; D007371:Interferon-gamma