Cross-regulation of TNF and IFN-alpha in autoimmune diseases.
Cytokines, most particularly TNF and type I IFN (IFN-alphabeta), have been long considered essential elements in the development of autoimmunity. Identification of TNF in the pathogenesis of rheumatoid arthritis and TNF antagonist therapy represent successes of immunology. IFN-alphabeta plays a major role in systemic lupus erythematosus (SLE), a prototype autoimmune disease characterized by a break of tolerance to nuclear components. Here, we show that TNF regulates IFN-alpha production in vitro at two levels. First, it inhibits the generation of plasmacytoid dendritic cells (pDCs), a major producer of IFN-alphabeta, from CD34+ hematopoietic progenitors. Second, it inhibits IFN-alpha release by immature pDCs exposed to influenza virus. Neutralization of endogenous TNF sustains IFN-alpha secretion by pDCs. These findings are clinically relevant, as five of five patients with systemic juvenile arthritis treated with TNF antagonists display overexpression of IFN-alpha-regulated genes in their blood leukocytes. These results, therefore, might provide a mechanistic explanation for the development of anti-dsDNA antibodies and lupus-like syndrome in patients undergoing anti-TNF therapy.
Palucka
A Karolina
AK
Baylor Institute for Immunology Research, 3434 Live Oak Street, Dallas, TX 75214, USA.
Blanck
Jean-Philippe
JP
Bennett
Lynda
L
Pascual
Virginia
V
Banchereau
Jacques
J
D001327:Autoimmune Diseases / Q000276:immunology*; D006801:Humans; D016898:Interferon-alpha / Q000502:physiology*; D014158:Transcription, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*
D016898:Interferon-alpha; D014409:Tumor Necrosis Factor-alpha
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