IFN-beta differentially regulates CD40-induced cytokine secretion by human dendritic cells.
We have previously shown that IFN-beta, a key cytokine associated with the early phase of the innate host defense, can prevent the generation of human Th1 cells. Specifically, we demonstrated that IFN-beta prevents the in vitro monocyte-derived mature dendritic cell (DC)-dependent differentiation of naive Th cells into IFN-gamma-secreting Th cells, as a result of its ability to inhibit DC IL-12 secretion. The goal of the present study was to identify how IFN-beta negatively regulates IL-12 secretion by DC. We report that in our Th cell differentiation model, DC IL-12 secretion is dependent on the CD40L/CD40 accessory pathway, and, utilizing a Th cell-free system, we find that IFN-beta inhibits anti-CD40 mAb-induced DC secretion of the p40 chain of the IL-12 heterodimer. In addition, we show that IFN-beta-mediated inhibition of CD40 signaling does not interfere with all signaling pathways emanating from CD40, since anti-CD40 mAb-induced DC IL-6 secretion is augmented by IFN-beta. Thus, our results demonstrate that signaling from CD40 is differentially regulated by IFN-beta. A second critical element of innate immunity involves the response against components of bacterial membranes such as LPS. DC respond to LPS by secreting IL-6 and IL-12. In contrast to CD40-dependent IL-6 and IL-12 secretion, we find that LPS-induced DC secretion of p40 IL-12 and IL-6 is not affected by IFN-beta. Our findings show that IFN-beta influences the generation of acquired immune responses through its regulation of CD40-dependent DC functions.
McRae
B L
BL
Committee on Immunology, Department of Pathology, Division of Biological Sciences, University of Chicago, IL 60637, USA.
Beilfuss
B A
BA
van Seventer
G A
GA
D000276:Adjuvants, Immunologic / Q000502:physiology*; D019013:CD40 Antigens / Q000502:physiology*; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism*; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism*; D004357:Drug Synergism; D006801:Humans; D016899:Interferon-beta / Q000502:physiology*; D018664:Interleukin-12 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism; D015850:Interleukin-6 / Q000096:biosynthesis / Q000378:metabolism; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000494:pharmacology; D015398:Signal Transduction / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology; D000093242:Interleukin-6 Inhibitors
D000276:Adjuvants, Immunologic; D019013:CD40 Antigens; D016207:Cytokines; D016899:Interferon-beta; D018664:Interleukin-12; D015850:Interleukin-6; D008070:Lipopolysaccharides; D000093242:Interleukin-6 Inhibitors