title: The p21ras protein as an intermediate signaling molecule in the IL-4-induced HLA-DR expression on normal and leukemic human myeloid cells.
abstract: We have previously demonstrated that the low number of interleukin-4 receptors (IL-4Rc) on HL-60 leukemia cells render this population susceptible to differentiation by IL-4. As it occurs with normal human monocytes, IL-4 induces the expression of HLA-DR surface antigens on HL-60 cells as well. The second messenger pathway(s) involved after the IL-4 stimulation leading to class II up-regulation has not been fully examined. Here we show that IL-4-induced class II antigen expression on the HL-60 cell line or normal human monocytes is calcium/calmodulin-independent since theophylline (TPH, a calmodulin inhibitor) does not block the IL-4 effect. In addition, the pyruvate kinase C (PKC) pathway does not seem to participate in the process either because in our system activation of PKC by 4 beta-phorbol 12 beta-myristate 13 alpha-acetate (PMA) is insufficient by itself to induce HLA-DR. We found, however, that a second messenger pathway can be mediated by a G protein system since IL-4 concomitantly induces class II and p21ras expression which can be successfully blocked by a highly specific anti-p21ras monoclonal antibody. In addition, using another p21ras inducer, the 5-azacytidine C (5-AzaC), we showed that this agent can also induce the expression of p21ras and class II, both of which can be inhibited by the same antibody. Thus, it appears that IL-4 selects the G protein system as a signaling pathway in order to exert its action for the induction of HLA-DR on human normal monocytes or M2 leukemia target cells. Since monocytes and macrophages participate in virtually all immune reactions, the regulation of class II induction is of obvious importance.
authors.affiliation: Institute of Molecular Biology and Biotechnology (IMBB), Crete, Greece.
authors.forename: S
authors.initials: S
authors.lastname: Vassiliadis
authors.forename: J
authors.initials: J
authors.lastname: Papamatheakis
mesh_terms: D001374:Azacitidine / Q000494:pharmacology; D002478:Cells, Cultured / Q000187:drug effects; D019204:GTP-Binding Proteins / Q000276:immunology*; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D006684:HLA-DR Antigens / Q000096:biosynthesis*; D006801:Humans; D015847:Interleukin-4 / Q000494:pharmacology*; D009000:Monocytes / Q000166:cytology; D016283:Proto-Oncogene Proteins p21(ras) / Q000502:physiology*; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction; D014407:Tumor Cells, Cultured / Q000187:drug effects; D015854:Up-Regulation
chemical_list: D006684:HLA-DR Antigens; D011994:Recombinant Proteins; D015847:Interleukin-4; D019204:GTP-Binding Proteins; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras); D001374:Azacitidine