The p21ras protein as an intermediate signaling molecule in the IL-4-induced HLA-DR expression on normal and leukemic human myeloid cells

Cell Immunol. 1992 Jul;142(2):426-33. doi: 10.1016/0008-8749(92)90302-6.


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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Azacitidine / pharmacology
  • Cells, Cultured / drug effects
  • GTP-Binding Proteins / immunology*
  • Gene Expression Regulation, Leukemic / drug effects
  • HLA-DR Antigens / biosynthesis*
  • Humans
  • Interleukin-4 / pharmacology*
  • Monocytes / cytology
  • Proto-Oncogene Proteins p21(ras) / physiology*
  • Recombinant Proteins / pharmacology
  • Signal Transduction*
  • Tumor Cells, Cultured / drug effects
  • Up-Regulation


  • HLA-DR Antigens
  • Recombinant Proteins
  • Interleukin-4
  • GTP-Binding Proteins
  • HRAS protein, human
  • Proto-Oncogene Proteins p21(ras)
  • Azacitidine