Inhibition of IL-10 protein synthesis induces major histocompatibility complex class II gene expression in class II-deficient patients.
Major histocompatibility complex (MHC) class II deficiency is an inherited autosomal recessive combined immunodeficiency, characterized by a lack of constitutive expression of the human leukocyte antigen (HLA) class II genes. The patients investigated in this study are histoidentical twin brothers with a new phenotype in MHC class II deficiency. Examination of HLA-D locus genes in their fractionated peripheral mononuclear cells (MNCs) revealed an unusual and uncoordinated mRNA pattern. Here we analyzed the distribution of pro- and anti-inflammatory cytokines expressed in these patients' adherent and nonadherent MNCs. We show that gene expression of IL-1 alpha, IL-1 beta, IL-6, granulocyte-colony-stimulating factor, and IL-10 was induced in both cell fractions, whereas increased mRNA levels of interferon-gamma and the inducible nitric oxide synthase were exclusively detected in the patients' nonadherent MNCs. As IL-10 is known to be able to downregulate transcription of MHC class II and expression of IL-10 in the patients' MNCs was increased, we investigated the regulatory function of this cytokine. Interestingly, inhibition of IL-10 protein synthesis with IL-10-specific antisense oligonucleotide DNA (IL-10-AS-ODN) induced HLA-D locus genes in these MHC class II-deficient patients. Exposure of the nonadherent cell fraction to IL-10-AS-ODN resulted in a profound induction of a previously absent DR beta 1 and DP alpha gene expression. HLA-DQ beta mRNA levels, however, were increased in both the adherent and the nonadherent MNC population. Albeit expression of HLA-D locus genes was inducible via inhibition of IL-10 translation, surface expression of HLA class II antigens on the patients' MNCs was essentially negative. The data presented support the concept of a coordinated network of pro- and anti-inflammatory cytokine regulation and this network obviously has a significant role in the cell-type-specific regulation of MHC class II expression.
Hauber
I
I
Institute of Clinical and Molecular Virology, University Erlangen Nürnberg, Germany. iahauber@viro.med
Wolf
H M
HM
Samstag
A
A
Pein
B
B
Kreil
T R
TR
Gulle
H
H
Fischer
M B
MB
Eibl
M M
MM
D002478:Cells, Cultured; D016207:Cytokines / Q000502:physiology; D005786:Gene Expression Regulation; D005802:Genes, MHC Class II; D006681:HLA-D Antigens / Q000378:metabolism*; D006801:Humans; D016753:Interleukin-10 / Q000096:biosynthesis*; D007963:Leukocytes, Mononuclear / Q000502:physiology; D008297:Male; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics
D016207:Cytokines; D006681:HLA-D Antigens; D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger; D016753:Interleukin-10