Differential regulation of DAP12 and molecules associated with DAP12 during host responses to mycobacterial infection.
DAP12 and its associating molecules MDL-1, TREM-1, and TREM-2 are the recently identified immune regulatory molecules, expressed primarily on myeloid cells including monocytes/macrophages, dendritic cells, NK cells, and neutrophils. However, little is known about the regulation of their expression during host antimicrobial responses. We have investigated the effect of pulmonary mycobacterial infection and type 1 cytokines on the expression of these molecules both in vivo and in vitro. While DAP12 was constitutively expressed at high levels in the lungs, the MDL-1, TREM-1, and TREM-2 molecules were inducible during mycobacterial infection. Their kinetic expression was correlated with that of the type 1 cytokines tumor necrosis factor alpha (TNF-alpha) and gamma interferon (IFN-gamma). In primary lung macrophage cultures, high constitutive levels of DAP12 and TREM-2 were not modulated by mycobacterial or type 1 cytokine exposure. In contrast, expression of both MDL-1 and TREM-1 was markedly induced by mycobacterial infection and such induction was inhibited by concurrent exposure to IFN-gamma. On mycobacterial infection of TNF-alpha(-/-) and IFN-gamma(-/-) mice in vivo or their lung macrophages in vitro, TNF-alpha was found to be critical for mycobacterially induced MDL-1, but not TREM-1, expression whereas IFN-gamma negatively regulated mycobacterially induced MDL-1 and TREM-1 expression. Our findings thus suggest that DAP12 and its associating molecules are differentially regulated by mycobacterial infection and type 1 cytokines and that MDL-1- and TREM-1-triggered DAP12 signaling may play an important role in antimicrobial type 1 immunity.
Aoki
Naoko
N
Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada L8N 3Z5.
Zganiacz
Anna
A
Margetts
Peter
P
Xing
Zhou
Z
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics*; D000818:Animals; D001483:Base Sequence; D016207:Cytokines / Q000096:biosynthesis; D018076:DNA, Complementary / Q000235:genetics; D005786:Gene Expression Regulation; D007371:Interferon-gamma / Q000172:deficiency / Q000235:genetics; D037181:Lectins, C-Type / Q000235:genetics; D008562:Membrane Glycoproteins / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009164:Mycobacterium Infections / Q000235:genetics* / Q000276:immunology*; D018410:Pneumonia, Bacterial / Q000235:genetics* / Q000276:immunology*; D011956:Receptors, Cell Surface / Q000235:genetics; D011971:Receptors, Immunologic / Q000235:genetics*; D000073871:Triggering Receptor Expressed on Myeloid Cells-1; D014409:Tumor Necrosis Factor-alpha / Q000172:deficiency / Q000235:genetics
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; C509771:CLEC5A protein, human; C509772:Clec5a protein, mouse; D016207:Cytokines; D018076:DNA, Complementary; D037181:Lectins, C-Type; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; C408842:TREM1 protein, human; C498716:Trem2 protein, mouse; D000073871:Triggering Receptor Expressed on Myeloid Cells-1; D014409:Tumor Necrosis Factor-alpha; C484963:Tyrobp protein, mouse; D007371:Interferon-gamma