Differential responsiveness to IFN-alpha and IFN-beta of human mature DC through modulation of IFNAR expression.
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-beta 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-beta 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-beta but only partial responsiveness to IFN-alpha, 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.
Severa
Martina
M
Department of Infectious, Parasitic and Immune-Mediated Diseases, Istituto Superiore di Sanità, 00161 Rome, Italy.
Remoli
Maria Elena
ME
Giacomini
Elena
E
Ragimbeau
Josiane
J
Lande
Roberto
R
Uzé
Gilles
G
Pellegrini
Sandra
S
Coccia
Eliana M
EM
D000911:Antibodies, Monoclonal / Q000494:pharmacology; D002478:Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D054357:Chemokine CXCL10; D019743:Chemokines, CXC / Q000502:physiology; D003713:Dendritic Cells / Q000187:drug effects*; D015536:Down-Regulation / Q000187:drug effects; D004731:Endotoxins / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D007369:Interferon Inducers / Q000494:pharmacology*; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000494:pharmacology*; D016899:Interferon-beta / Q000494:pharmacology*; D008565:Membrane Proteins / Q000096:biosynthesis* / Q000235:genetics; D009000:Monocytes / Q000166:cytology; D011070:Poly I-C / Q000494:pharmacology; D053633:Receptor, Interferon alpha-beta; D017471:Receptors, Interferon / Q000096:biosynthesis* / Q000235:genetics; D011994:Recombinant Proteins / Q000494:pharmacology; D050794:STAT1 Transcription Factor / Q000502:physiology; D050795:STAT2 Transcription Factor / Q000502:physiology; D014158:Transcription, Genetic
D000911:Antibodies, Monoclonal; C114753:CXCL10 protein, human; D054357:Chemokine CXCL10; D019743:Chemokines, CXC; D004731:Endotoxins; C507964:IFNAR1 protein, human; C508033:IFNAR2 protein, human; D007369:Interferon Inducers; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D008565:Membrane Proteins; D017471:Receptors, Interferon; D011994:Recombinant Proteins; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050795:STAT2 Transcription Factor; C494084:STAT2 protein, human; D053633:Receptor, Interferon alpha-beta; C044101:endotoxin, Escherichia coli; D016899:Interferon-beta; D011070:Poly I-C