Monocytes are differentially activated through HLA-DR, -DQ, and -DP molecules via mitogen-activated protein kinases.
When HLA-DR, -DQ, and -DP were cross-linked by solid-phase mAbs, monocytes produced monokines and only anti-DR markedly activated mitogen-activated protein (MAP) kinase extracellular signal-related kinase, whereas anti-DR, anti-DQ, and anti-DP all activated MAP kinase p38. Activation of extracellular signal-related kinase was not inhibited by neutralizing Ab to TNF-alpha. Anti-DR and DR-restricted T cells stimulated monocytes to produce relatively higher levels of proinflammatory monokines, such as IL-1beta, whereas anti-DQ/DP and DQ-/DP-restricted T cells stimulated higher levels of anti-inflammatory monokine IL-10. IL-10 production was abrogated by the p38 inhibitor SB203580, but rather enhanced by the MAP/extracellular signal-related kinase kinase-I-specific inhibitor PD98059, whereas IL-1beta was only partially abrogated by SB203580 and PD98059. Furthermore, DR-restricted T cells established from PBMC, which are reactive with mite Ags, purified protein derivative, and random 19-mer peptides, exhibited a higher IFN-gamma:IL-4 ratio than did DQ- or DP-restricted T cells. These results indicate that HLA-DR, -DQ, and -DP molecules transmit distinct signals to monocytes via MAP kinases and lead to distinct monokine activation patterns, which may affect T cell responses in vivo. Thus, the need for generation of a multigene family of class II MHC seems apparent.
Matsuoka
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Department of Neuroscience and Immunology, Division of Immunogenetics, Kumamoto University Graduate School of Medical Sciences, Honjo, Kumamoto, Japan.
Tabata
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Matsushita
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D000328:Adult; D000595:Amino Acid Sequence; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D002999:Clone Cells; D018920:Coculture Techniques; D004640:Emetine / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects / Q000276:immunology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D006681:HLA-D Antigens / Q000276:immunology / Q000502:physiology*; D006682:HLA-DP Antigens / Q000276:immunology / Q000502:physiology; D006683:HLA-DQ Antigens / Q000276:immunology / Q000502:physiology; D006684:HLA-DR Antigens / Q000276:immunology / Q000502:physiology; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000276:immunology*; D008301:Maleimides / Q000494:pharmacology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008969:Molecular Sequence Data; D009000:Monocytes / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism*; D015846:Monokines / Q000096:biosynthesis / Q000378:metabolism; D010455:Peptides / Q000276:immunology / Q000494:pharmacology; D047428:Protein Kinase Inhibitors; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology / Q000378:metabolism
D000911:Antibodies, Monoclonal; D004791:Enzyme Inhibitors; D005419:Flavonoids; D006681:HLA-D Antigens; D006682:HLA-DP Antigens; D006683:HLA-DQ Antigens; D006684:HLA-DR Antigens; D007211:Indoles; D008301:Maleimides; D015846:Monokines; D010455:Peptides; D047428:Protein Kinase Inhibitors; D011500:Protein Synthesis Inhibitors; D020928:Mitogen-Activated Protein Kinases; C070515:bisindolylmaleimide I; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; D004640:Emetine