Abstract
Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a member of the four-helix bundle family of cytokines/growth factors which exhibit several activities. It is a hematopoietic growth factor, a cytokine involved in inflammatory and immune processes, an adjunct for cancer therapy, and an anti-tumor immunomodulator. Studies of interactions between GM-CSF and its receptor and identification of small peptides presenting binding capacity to the receptor are important goals for the development of GM-CSF analogs. Here we describe the study of two cyclic peptides, 1785 and 1786, developed based on structural analysis of the GM-CSF region mimicked by anti-anti-GM-CSF recombinant antibody 23.2. These peptides were designed to structurally mimic the positions of specific residues on the B and C helices of human GM-CSF implicated in receptor binding and bioactivity. Both 1785 and 1786 were specifically recognized by polyclonal anti-GM-CSF antibody (stronger for 1786 than 1785). 1786 also competitively inhibited binding of GM-CSF to the GM-CSF receptor on HL-60 cells and demonstrated antagonist bioactivity, as shown by its reversal of GM-CSF's ability to inhibit apoptosis of the GM-CSF-dependent cell line MO7E. These studies support the role of residues on the GM-CSF B and C helices in receptor binding and bioactivity and suggest strategies for mimicking binding sites on four-helix bundle proteins with cyclic peptides.
Highlights
Granulocyte-macrophage colony-stimulating factor (GMCSF)1 is a hematopoietic growth factor and a cytokine involved in many inflammatory and immune processes
The high affinity GM-CSFR is comprised of an ␣ chain (GM-CSFR␣) specific for Granulocyte-macrophage colony-stimulating factor (GM-CSF) [20], and a  chain (c), which can associate with the IL-3 and IL-5 receptor ␣ chains [21]
The high affinity receptor (GMCSFR␣ and c) appears to be the signal-transducing unit [25, 26], with a sequential binding of GM-CSF to GM-CSFR␣ followed by binding to c postulated
Summary
Granulocyte-macrophage colony-stimulating factor (GMCSF) is a hematopoietic growth factor and a cytokine involved in many inflammatory and immune processes. GM-CSF activates antigen-presenting cells (monocytes, macrophages, and dendritic cells), increases major histocompatibility complex class II expression-enhancing antigen presentation, and increases macrophage anti-tumor activity [1]. GM-CSF enhances the immunogenicity of tumor cells when expressed by them, resulting in induction of protective anti-tumor immunity, while other cytokines such as IL-2, IL-4, IL-5, IL-6, ␥-interferon, or tumor necrosis factor-␣ are less effective [4]. The high affinity GM-CSFR is comprised of an ␣ chain (GM-CSFR␣) specific for GM-CSF [20], and a  chain (c), which can associate with the IL-3 and IL-5 receptor ␣ chains [21]. The high affinity receptor (GMCSFR␣ and c) appears to be the signal-transducing unit [25, 26], with a sequential binding of GM-CSF to GM-CSFR␣ followed by binding to c postulated
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