Type I interferons inhibit interleukin-10 production in activated human monocytes and stimulate IL-10 in T cells: implications for Th1-mediated diseases.
Type I interferons (IFNs) directly induce development of Th1 cells. However, IFN-alpha and IFN-beta should generate Th2 cells because these IFNs induce interleukin-10 (IL-10) and block secretion of IFN-gamma. We hypothesized that paradoxical effects of IFNs on Th1-mediated immunity could be from monocyte-specific and T cell-specific IL-10 regulation. We demonstrate that IFN-alpha and IFN-beta inhibit IL-10 mRNA and protein production by activated monocytes but stimulate IL-10 production by activated T cells from the same healthy donors. Without IFN-beta, Staphylococcus aureus, Cowan strain I (SAC)-activated monocytes secreted 15-fold more IL-10 than phorbol myristate acetate (PMA) anti-CD3-activated T cells. With IFN-beta, the two subsets had nearly equivalent secretion. Prostaglandin (PGE) and other cAMP agonists had subset-specific effects on IL-10 production opposite to IFN-beta. The differential IFN-beta effect on transcriptional regulation of IL-10 in monocytes and T cells was from lineage-specific modification of RNA stability. IFN-beta decreased the half-life of IL-10 mRNA in activated monocytes but prolonged the half-life in activated T cells. Subset-specific IL-10 regulation has important implications for Th1-mediated disease. When activated macrophages and microglia are in excess, as in rheumatoid joints or possibly in chronic multiple sclerosis brain lesions, IFNs may inhibit overall IL-10 production and worsen disease. When T cells outnumber monocytes, IFN-beta will induce IL-10 and ameliorate Th1-mediated disease.
Feng
Xuan
X
Department of Neurology, The University of Chicago, Chicago, IL 60637, USA.
Yau
Douglas
D
Holbrook
Christopher
C
Reder
Anthony T
AT
D002478:Cells, Cultured; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D007370:Interferon Type I / Q000494:pharmacology*; D016898:Interferon-alpha / Q000494:pharmacology; D016899:Interferon-beta / Q000494:pharmacology; D016753:Interleukin-10 / Q000096:biosynthesis* / Q000235:genetics; D008213:Lymphocyte Activation; D009000:Monocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D013211:Staphylococcus aureus / Q000235:genetics; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology*
D007370:Interferon Type I; D016898:Interferon-alpha; D012333:RNA, Messenger; D011994:Recombinant Proteins; D016753:Interleukin-10; D016899:Interferon-beta