TNF-alpha, IL-6, and IL-1 expression is inhibited by GAS6 in monocytes/macrophages

Gas6 is able to inhibit pro-inflammatory cytokine secretion by macrophages acting on Mer receptor; the pathway involved is mediated by PI3K, Akt, GSK3β, and NFκB. GAS6 protein has been described to be involved in immune modulation in vitro and in vivo. Some of these effects are probably mediated through the involvement of monocytes/macrophages. To understand the role of GAS6 in modulating the immune response, we evaluated the effect on cytokine secretion by monocytes/macrophages and the molecular pathways involved. GAS6 inhibits TNF-α and IL-6 secretion by LPS-stimulated U937 cells and monocytes/machrophages. We evidenced that among GAS6 receptors, only Mer (but not Axl or Tyro3) is expressed on differentiated U937 cells, and its activation is responsible for the reduction of cytokine expression. In immunoblot analysis, Mer was activated after GAS6 stimulation, giving rise to an increased phosphorylation of Akt. We also observed GSK3β phosphorylation and consequent inhibition of NF-κB nuclear translocation. Therefore, GAS6 modulates macrophage cytokine secretion, triggering an “anti-inflammatory pathway” involving PI3K/Akt/GSK3β and NF-κB.