ISOTYPE-SPECIFIC REGULATION OF MHC CLASS-II GENE-EXPRESSION IN HUMAN MONOCYTES BY EXOGENOUS AND ENDOGENOUS TUMOR-NECROSIS-FACTOR

The control of expression of MHC class II molecules on antigen-present ing cells is important for the induction of immunity, while aberrant e xpression of these molecules plays a role in the immunopathology of au toimmune diseases. This study explored the role of tumor necrosis fact or alpha (TNF) in controlling the level of HLA class II mRNA in human monocytes. Exposure of monocytes to exogenous recombinant TNF (rTNF) s electively up-regulated DR (alpha-mRNA but not DP or DQ alpha-mRNA. In hibitors of TNF synthesis, pentoxifylline (PTX) and thalidomide, inhib ited TNF mRNA accumulation in LPS-activated monocytes and down-regulat ed DR mRNA but not DP or DQ mRNA. The inhibitory effect of anti-TNF mo noclonal antibody (MAb) indicated that endogenously generated TNF acte d extracellularly. Anti-p75 TNF-R2 receptor and to a lesser extent ant i-p55 TNF-R1 MAbs inhibited TNF-mediated up-regulation of DR mRNA and TNF mRNA. Taken together, this implies that endogenously generated TNF plays a role in controlling isotype-specific MHC class II gene expres sion in human monocytes/macrophages. These results may have some impli cations for anti-tumor response and autoimmunity.