Involvement of class II MHC molecules in the LPS-induction of IL-1/TNF secretions by human monocytes. Quantitative differences at the polymorphic level.
Anti-class II ag mAb (DR and DQ) inhibited, in a dose-dependent manner, LPS-induced IL-1 and TNF secretions from human monocytes (34 to 95% inhibition). The potentiating effect of IFN-gamma on LPS-induced TNF secretion (15.3 +/- 0.7 to 44 +/- 0.6 ng/ml) was also blocked by anti-class II ag mAb (44 +/- 0.6 to 0.3 +/- 0.03 ng/ml). We also report a relationship between interindividual differences in monocyte IL-1 and TNF secretions and the HLA-D-encoded genetic polymorphism. Heterozygotes were, in general, higher secretors of those cytokines than homozygotes. Analysis of these secretions in heterozygotes demonstrated a differential effect of certain haplotype combinations (i.e., DR2-DR4 vs DR2-DR3) that could be arbitrarily characterized as being "low" or "high" secretors (6,230 +/- 2,950 vs 13,029 +/- 6,541 cpm for IL-1, and 12 +/- 10 vs 25 +/- 15 ng/ml for TNF, p = 0.006 and 0.048). DR-associated Dw subtypes appeared to account for differences within certain haplotype combinations (Dw18 vs Dw19 in DRw13/DR4) (11,227 +/- 3,648 vs 17,166 +/- 3,176 cpm for IL-1, and 13 +/- 9 vs 25 +/- 10 ng/ml for TNF, p = 0.02 and 0.047). Interindividual differences were better explained by differences in LPS sensitivity than by differences in the kinetics of secretion and related not to the secretory process itself but to the rate of cytokine synthesis. Finally, there were no relationships between high secretor genotypes and IDD high risk genotypes. Thus, we conclude that, a) LPS-induced IL-1 and TNF secretions are, at least in part, regulated by class II MHC molecules, b) that HLA-D region-encoded genetic polymorphism accounts for interindividual differences in these secretions, and c) that the HLA-associated risk to develop IDD is not explained by these cytokine secretory differences as previously proposed.
Santamaria
P
P
Department of Medicine, University of Minnesota, Minneapolis 55455.
Gehrz
R C
RC
Bryan
M K
MK
Barbosa
J J
JJ
D000328:Adult; D000818:Animals; D003922:Diabetes Mellitus, Type 1 / Q000145:classification / Q000276:immunology / Q000378:metabolism; D005260:Female; D006681:HLA-D Antigens / Q000235:genetics / Q000276:immunology*; D006650:Histocompatibility Testing; D006801:Humans; D007375:Interleukin-1 / Q000096:biosynthesis*; D007700:Kinetics; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008875:Middle Aged; D009000:Monocytes / Q000276:immunology / Q000378:metabolism*; D010641:Phenotype; D011110:Polymorphism, Genetic; D012307:Risk Factors; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
D006681:HLA-D Antigens; D007375:Interleukin-1; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha