title: GM-CSF signalling boosts dramatically IL-1 production.
abstract: GM-CSF is mostly known for its capacity to promote bone marrow progenitor differentiation, to mobilize and mature myeloid cells as well as to enhance host immune responses. However the molecular actions of GM-CSF are still poorly characterized. Here we describe a new surprising facet of this "old" growth factor as a key regulator involved in IL-1β secretion. We found that IL-1β release, a pivotal component of the triggered innate system, is heavily dependent on the signaling induced by GM-CSF in such an extent that in its absence IL-1β is only weakly secreted. GM-CSF synergizes with LPS for IL-1β secretion mainly at the level of pro-IL-1β production via strengthening the NF-κB signaling. In addition, we show that expression of Rab39a, a GTPase required for caspase-1 dependent IL-1β secretion is greatly augmented by LPS and GM-CSF co-stimulation suggesting a potential GM-CSF contribution in enhancing IL-1β exocytosis. The role of GM-CSF in regulating IL-1β secretion is extended also in vivo, since GM-CSF R-/- mice are more resistant to LPS-mediated septic shock. These results identify GM-CSF as a key regulator of IL-1β production and indicate GM-CSF as a previously underestimated target for therapeutic intervention.
authors.affiliation: Nanyang Technological University, School of Biological Sciences, Singapore.
authors.forename: Hanif Javanmard
authors.initials: HJ
authors.lastname: Khameneh
authors.forename: Siti Aminah Bte Mohammad
authors.initials: SA
authors.lastname: Isa
authors.forename: Lin
authors.initials: L
authors.lastname: Min
authors.forename: Fam Wee
authors.initials: FW
authors.lastname: Nih
authors.forename: Christiane
authors.initials: C
authors.lastname: Ruedl
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001854:Bone Marrow Cells / Q000187:drug effects / Q000378:metabolism; D020170:Caspase 1 / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000187:drug effects / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005786:Gene Expression Regulation; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology*; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012772:Shock, Septic / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D016328:NF-kappa B; D012333:RNA, Messenger; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor; D014409:Tumor Necrosis Factor-alpha; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D020170:Caspase 1