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 pr otein (MAP) kinase extracellular signal-related kinase, whereas anti-DR, an ti-DQ, and anti-DP all activated MAP kinase p38. Activation of extracellula r signal-related kinase was not inhibited by neutralizing Ab to TNF-alpha. Anti-DR and DR-restricted T cells stimulated monocytes to produce relativel y higher levels of proinflammatory monokines, such as IL-1 beta, whereas an ti-DQ/DP and DQ-/DP-restricted T cells stimulated higher levels of anti-inf lammatory monokine IL-10. IL-10 production was abrogated by the p38 inhibit or SB203580, but rather enhanced by the MAP/extracellular signal-related ki nase kinase-I-specific inhibitor PD98059, whereas IL-1 beta was only partia lly abrogated by SB203580 and PD98059, Furthermore, DR-restricted T cells e stablished from PBMC, which are reactive with mite Ags, purified protein de rivative, and random 19-mer peptides, exhibited a higher IFN-gamma :IL-4 ra tio 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 k inases and lead to distinct monokine activation patterns, which may affect T cell responses in vivo. Thus, the need for generation of a multigene fami ly of class II MHC seems apparent.