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-1ß secretion. We found that IL-1ß 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-1ß is only weakly secreted. GM-CSF synergizes with LPS for IL-1ß secretion mainly at the level of pro-IL-1ß production via strengthening the NF-κB signaling. In addition, we show that expression of Rab39a, a GTPase required for caspase-1 dependent IL-1ß secretion is greatly augmented by LPS and GM-CSF co-stimulation suggesting a potential GM-CSF contribution in enhancing IL-1ß exocytosis. The role of GM-CSF in regulating IL-1ß 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-1ß production and indicate GM-CSF as a previously underestimated target for therapeutic intervention.
Subject(s)
Gene Expression Regulation , Granulocyte-Macrophage Colony-Stimulating Factor/pharmacology , Interleukin-1beta/metabolism , Receptors, Granulocyte-Macrophage Colony-Stimulating Factor/physiology , Animals , Blotting, Western , Bone Marrow Cells/drug effects , Bone Marrow Cells/metabolism , Caspase 1/genetics , Caspase 1/metabolism , Cells, Cultured , Dendritic Cells/drug effects , Dendritic Cells/metabolism , Enzyme-Linked Immunosorbent Assay , Interleukin-1beta/genetics , Lipopolysaccharides/pharmacology , Mice , Mice, Inbred C57BL , Mice, Knockout , NF-kappa B/genetics , NF-kappa B/metabolism , RNA, Messenger/genetics , Reverse Transcriptase Polymerase Chain Reaction , Shock, Septic/etiology , Shock, Septic/metabolism , Shock, Septic/pathology , Signal Transduction , Tumor Necrosis Factor-alpha/metabolismABSTRACT
During priming, CD8(+) T lymphocytes can induce robust maturation of dendritic cells (DCs) in a CD40-independent manner by secreting licensing factor(s). In this study, we isolate this so-far elusive licensing factor and identify it, surprisingly, as GM-CSF. This provides a new face for an old factor with a well-known supporting role in DC development and recruitment. Signaling through the GM-CSFR in ex vivo-purified DCs upregulated the expression of costimulatory molecules more efficiently than did any tested TLR agonist and provided a positive feedback loop in the stimulation of CD8(+) T cell proliferation. Combined with a variety of microbial stimuli, GM-CSF supports the formation of potent "effector" DCs capable of secreting a variety of proinflammatory cytokines that guide the differentiation of T cells during the immune response.
