Resistance of rheumatoid synovial dendritic cells to the immunosuppressive effects of IL-10.
IL-10 down-regulates the APC function of many dendritic cells (DC), including human peripheral blood (PB) DC. In rheumatoid arthritis (RA), synovial fluid (SF) DC express markers of differentiation and are effective APC despite abundant synovial IL-10. The regulation of DC responsiveness to IL-10 was therefore examined by comparing the effect of IL-10 on normal PB and RA SF DC. Whereas IL-10 down-modulated APC function and MHC class II and B7 expression of PB DC, IL-10 had no such effect on SF DC. Since SF DC have differentiated in vivo in the presence of proinflammatory cytokines, PB DC were cocultured in the presence of IL-10 and either GM-CSF, IL-1beta, TNF-alpha, IL-6, or TGF-beta. GM-CSF, IL-1beta, and TNF-alpha were all able to restore APC function. Whereas the effects of IL-10 on PB DC were shown to be mediated by IL-10R1, neither PB nor RA SF DC constitutively expressed IL-10R1 mRNA or detectable surface protein. In contrast, IL-10R1 protein was demonstrated in PB and SF DC whole cell lysates, suggestive of predominant intracellular localization of the receptor. Thus, DC responsiveness to IL-10 may be regulated through modulation of cell surface IL-10R1 expression or signaling.
MacDonald
K P
KP
Centre for Immunology and Cancer Research, University of Queensland, Princess Alexandra Hospital, Brisbane, Australia.
Pettit
A R
AR
Quinn
C
C
Thomas
G J
GJ
Thomas
R
R
D017951:Antigen Presentation / Q000276:immunology; D000938:Antigen-Presenting Cells / Q000276:immunology; D015703:Antigens, CD / Q000096:biosynthesis; D001172:Arthritis, Rheumatoid / Q000276:immunology*; D051940:B7-2 Antigen; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D015536:Down-Regulation / Q000276:immunology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000502:physiology; D006684:HLA-DR Antigens / Q000096:biosynthesis; D006801:Humans; D007113:Immunity, Innate; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007375:Interleukin-1 / Q000502:physiology; D016753:Interleukin-10 / Q000037:antagonists & inhibitors / Q000502:physiology*; D008562:Membrane Glycoproteins / Q000096:biosynthesis; D009000:Monocytes / Q000276:immunology; D012333:RNA, Messenger / Q000096:biosynthesis; D018123:Receptors, Interleukin / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D053701:Receptors, Interleukin-10; D015398:Signal Transduction / Q000276:immunology; D013583:Synovial Membrane / Q000276:immunology* / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology
D015703:Antigens, CD; D051940:B7-2 Antigen; C497964:CD86 protein, human; D006684:HLA-DR Antigens; D007166:Immunosuppressive Agents; D007375:Interleukin-1; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D018123:Receptors, Interleukin; D053701:Receptors, Interleukin-10; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D016178:Granulocyte-Macrophage Colony-Stimulating Factor