Interaction of GM-CSF and IL-3 with the common 3-chain of their receptors

Abstract:Human granulocyte-macrophage colony-stimu-lating factor (GM-CSF) and interleukin (IL-3) are cytoki-nes 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 3 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 pathologi-cal conditions, we are seeking to define the structural elements required for ligand/receptor and receptor/re-ceptor contact and their role in cellular activation. To this end we have identified a conserved motif in the first helix of GM-CSF, G1u21 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 selec-tive deficiency in interaction with the chain of the receptor and suggests that similar antagonists for IL-S and IL-5 are also feasible. Complementary mutagenesis studies on the receptor chain have identified the puta. tive B’-C ’ loop in the membrane-proximal domain as being critical for the high affinity binding of GM-CSF but not IL-S. Characterization of the specificity of sites of interaction between the ligands and receptors may per-mit the design of specific or generic antagonists that may have important therapeutic imphications.J. Leukoc. Biol