title: Macrophage-colony stimulating factor and interleukin-34 induce chemokines in human whole blood.
abstract: The aim of this study is to investigate if macrophage-colony stimulating factor (M-CSF) or interleukin-34 (IL-34) induces cytokines or chemokines using human whole blood (HWB) and if an M-CSF- or IL-34-induced cytokine or chemokine production from HWB is inhibited by soluble M-CSF receptor or c-FMS kinase inhibitors. Among eight cytokines or growth factors tested, only IL-6 level was increased by up to 6-fold by M-CSF or IL-34 in HWB. In contrast, chemokine levels (IP-10/CXCL10, IL-8/CXCL8, and MCP-1/CCL2) were dramatically increased by M-CSF or IL-34 in HWB while exhibiting a large variation among donors. Variability of the MCP-1 signal induced by M-CSF or IL-34 was relatively less among donors compared to the IP-10 and IL-8 signals. The elevation of these chemokine levels was significantly decreased by soluble M-CSF receptor, indicating the elevation of these chemokines was mediated by M-CSF or IL-34. Furthermore, GW2580, a c-FMS kinase inhibitor, inhibited the induction of MCP-1 by M-CSF or IL-34 in a concentration dependent manner. These indicate MCP-1 is the most appropriate chemokine target for a chemokine release assay to evaluate the potency of c-FMS kinase inhibitors and MCP-1 release assay using HWB would be useful, relevant tool for translational pharmacology of c-FMS kinase inhibitors.
authors.affiliation: Discovery Biology, Global Research and Development, St. Louis Laboratories, Pfizer Inc., 700 Chesterfield Parkway West, Chesterfield, MO 63017, USA. hiroyuki_eda@ajinomoto.com
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Eda
authors.forename: Jian
authors.initials: J
authors.lastname: Zhang
authors.forename: Robert H
authors.initials: RH
authors.lastname: Keith
authors.forename: Marshall
authors.initials: M
authors.lastname: Michener
authors.forename: David R
authors.initials: DR
authors.lastname: Beidler
authors.forename: Joseph B
authors.initials: JB
authors.lastname: Monahan
mesh_terms: D000840:Anisoles / Q000494:pharmacology; D018925:Chemokines / Q000096:biosynthesis* / Q000097:blood; D006801:Humans; D007378:Interleukins / Q000502:physiology*; D016173:Macrophage Colony-Stimulating Factor / Q000502:physiology*; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology
chemical_list: C506269:5-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)pyrimidine-2,4-diamine; D000840:Anisoles; D018925:Chemokines; C529076:IL34 protein, human; D007378:Interleukins; D011743:Pyrimidines; D016173:Macrophage Colony-Stimulating Factor