GM-CSF Signalling Boosts Dramatically IL-1Production

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-1 beta secretion. We found that IL-1 beta 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-1 beta is only weakly secreted. GM-CSF synergizes with LPS for IL-1 beta secretion mainly at the level of pro-IL-1 beta production via strengthening the NF-kappa B signaling. In addition, we show that expression of Rab39a, a GTPase required for caspase-1 dependent IL-1 beta secretion is greatly augmented by LPS and GMCSF co-stimulation suggesting a potential GM-CSF contribution in enhancing IL-1 beta exocytosis. The role of GM-CSF in regulating IL-1 beta 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-1 beta production and indicate GM-CSF as a previously underestimated target for therapeutic intervention.