Differential regulation of the expression of transporters associated with antigen processing, TAP1 and TAP2, by cytokines and lipopolysaccharide in primary human macrophages.
OBJECTIVE
Using microarray technique we analysed global changes in gene expression of interferon-y treated primary macrophages. Among the differential expressed genes identified we focussed on the expression of the transporters associated with antigen processing, TAP1 and TAP2, which are involved in the antigen presentation via MHC class 1. Patients suffering from TAP deficiency syndrome have clinical manifestations including recurrent bacterial infections of the respiratory tract and chronic necrotizing granulomatous skin lesions. This is one reason why the regulation of TAP gene expression in antigen presenting cells such as macrophages might provide important general insights into the generation of cellular immune response to multiple pathogens. Additionally IFN-alpha is important in adjuvant tumortherapie although the working mechanisms are unknown. Because of the possibility of the TAPs to be involved in these mechanisms we studied the expression of these transporters in human macrophages after stimulation with pro-inflammatory mediators.


METHODS
Monocyte derived macrophages were treated for 24 h with either interferon-gamma, interferon-alpha, interleukin-1 (each 100 U/ml) or lipopolysaccharide (1 microg/ml).


METHODS
IFN-gamma induced gene expression was analysed using microarray technique. TAP expression was investigated by RT-PCR, northern blot- and western blot analysis.


RESULTS
TAP1 and TAP2 were constitutively expressed at a low level. IFN-gamma upregulated the expression of both transporters. LPS caused an increase similar to the effect of IFN-gamma. Treatment with IFN-a stimulated also the expression, however, less than IFN-y. In contrast, IL-1beta stimulation had no effect.


CONCLUSIONS
Our data show that the transporters associated with antigen presentation are differentially regulated by pro-inflammatory mediators in human macrophages. The finding that IFN-alpha stimulates the expression of proteins involved in cytotoxic effector functions of macrophages contributes to the understanding of the immunoregulatory role of type 1 interferons and may help to explain the efficacy of IFN-alpha in the treatment of tumors.
Schiffer
R
R
rschiffer@ukaachen.de
Baron
J
J
Dagtekin
G
G
Jahnen-Dechent
W
W
Zwadlo-Klarwasser
G
G
D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D000071450:ATP Binding Cassette Transporter, Subfamily B, Member 3; D018528:ATP-Binding Cassette Transporters / Q000235:genetics* / Q000378:metabolism; D017951:Antigen Presentation; D015152:Blotting, Northern; D002478:Cells, Cultured; D016207:Cytokines / Q000276:immunology*; D005786:Gene Expression Regulation; D006801:Humans; D016898:Interferon-alpha / Q000276:immunology; D007371:Interferon-gamma / Q000276:immunology; D007375:Interleukin-1 / Q000276:immunology; D008070:Lipopolysaccharides / Q000276:immunology*; D008264:Macrophages / Q000276:immunology / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015854:Up-Regulation
D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D000071450:ATP Binding Cassette Transporter, Subfamily B, Member 3; D018528:ATP-Binding Cassette Transporters; D016207:Cytokines; D016898:Interferon-alpha; D007375:Interleukin-1; D008070:Lipopolysaccharides; D012333:RNA, Messenger; C073119:TAP1 protein, human; C071692:TAP2 protein, human; D007371:Interferon-gamma