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Published online before print April 19, 2006

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(Journal of Leukocyte Biology. 2006;79:1286-1294.)
© 2006 by Society for Leukocyte Biology

Differential responsiveness to IFN- and IFN-ß of human mature DC through modulation of IFNAR expression

Martina Severa^*, Maria Elena Remoli^*, Elena Giacomini^*, Josiane Ragimbeau, Roberto Lande^*, Gilles Uzé, Sandra Pellegrini and Eliana M. Coccia^*,1

^* Department of Infectious, Parasitic and Immune-Mediated Diseases, Istituto Superiore di Sanità, Rome, Italy;
CNRS UMR 5124, Montpellier, France; and
Unit of Cytokine Signaling, CNRS URA 1961, Institut Pasteur, Paris, France

¹Correspondence: Department of Infectious, Parasitic and Immune-Mediated Diseases, Istituto Superiore di Sanità, 00161 Rome, Italy. E-mail: e.coccia{at}iss.it

In human monocyte-derived dendritic cells (DC), infection with Mycobacterium tuberculosis and viruses or stimulation with Toll-like receptor type 3 and 4 agonists causes the release of type I interferon (IFN). Here, we describe that the IFN-ß released upon stimulation with lipopolysaccharide (LPS) or polyinosinic:polycytidylic acid (poly I:C) is responsible for a rapid and sustained signal transducer and activator of transcription 1 and 2 activation and expression of IFN-stimulated genes, such as the transcription factor IFN regulatory factor 7 and the chemokine CXC chemokine ligand 10. The autocrine production of IFN-ß from LPS and poly I:C-matured DC (mDC) induced a temporary saturation of the response to type I IFN and a marked decline in the level of the two IFN receptor (IFNAR) subunits. It is interesting that we found that upon clearing of the released cytokines, LPS-stimulated DC reacquired full responsiveness to IFN-ß but only partial responsiveness to IFN-, and their maturation process was unaffected. Monitoring of surface and total levels of the receptor subunits showed that maximal expression of IFNAR2 resumed within 24 h of clearing, and IFNAR1 expression remained low. Thus, mDC can modulate their sensitivity to two IFN subtypes through a differential regulation of the IFNAR subunits.

Key Words: type I IFN • cytokine receptor • TLR • LPS

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