INTERACTION OF GM-CSF AND IL-3 WITH THE COMMON BETA-CHAIN OF THEIR RECEPTORS

Human granulocyte macrophage colony-stimulating factor (GM-CSF) and interleukin (IL-3) are cytokines active in both normal and abnormal hemopoiesis, inflammation, and immunity, Their biological activity is mediated via receptors that comprise a ligand-specific a chain and a beta chain that is common to the GM-CSF, IL-3, and IL-5 receptors, To understand the mechanism of action of GM-CSF and IL-3 in both normal and pathological conditions, we are seeking to define the structural elements required for ligand/receptor and receptor/receptor contact and their role in cellular activation, To this end we have identified a conserved motif in the first helix of GM-CSF, Glu(21) that is critical for high affinity binding and biological activity, Charge-reversal mutagenesis of this residue generates a GM-CSF analogue that is devoid of biological activity and can antagonize the activity of wild-type GM-CSF, This probably results from the selective deficiency in interaction with the beta chain of the receptor and suggests that similar antagonists for IL-3 and IL-5 are also feasible, Complementary mutagenesis studies on the receptor beta chain have identified the putative B'-C' loop in the membrane-proximal domain as being critical for the high affinity binding of GM-CSF but not IL-3, Characterization of the specificity of sites of interaction between the ligands and receptors may permit the design of specific or generic antagonists that may have important therapeutic implications.