Abstract
BackgroundGranulysin is an antimicrobial and proinflammatory protein with several isoforms. While the 9 kDa isoform is a well described cytolytic molecule with pro-inflammatory activity, the functions of the 15 kDa isoform is less well understood. Recently it was shown that 15 kDa Granulysin can act as an alarmin that is able to activate monocytes and immature dendritic cells. Granulocyte Macrophage Colony Stimulating Factor (GM-CSF) is a growth factor widely used in immunotherapy both for in vivo and ex vivo applications, especially for its proliferative effects.MethodsWe analyzed gene expression profiles of monocytes cultured with 15 kDa Granulysin or GM-CSF for 4, 12, 24 and 48 hours to unravel both similarities and differences between the effects of these stimulators.ResultsThe analysis revealed a common signature induced by both factors at each time point, but over time, a more specific signature for each factor became evident. At all time points, 15 kDa Granulysin induced immune response, chemotaxis and cell adhesion genes. In addition, only 15 kDa Granulsyin induced the activation of pathways related to fundamental dendritic cell functions, such as co-stimulation of T-cell activation and Th1 development. GM-CSF specifically down-regulated genes related to cell cycle arrest and the immune response. More specifically, cytokine production, lymphocyte mediated immunity and humoral immune response were down-regulated at late time points.ConclusionThis study provides important insights on the effects of a novel agent, 15 kDa granulysin, that holds promise for therapeutic applications aimed at the activation of the immune response.
Highlights
Granulysin is an antimicrobial and proinflammatory protein with several isoforms
Principal component analysis of the entire dataset (Figure 1a) revealed that Granulocyte Macrophage Colony Stimulating Factor (GM-CSF) and 15 kDa Granulysin induced a response in monocytes that was similar at early time points (4 hours) but strongly differed at later time points (12, 24 and 48 hours)
principal component (PC) #2, which accounted for 14.8% of the variability, split the GM-CSF and Granulysin samples into two distinct groups at later time points, indicating that the differences between the GM-CSFand Granulysin-cultured monocytes became more evident at later time points
Summary
Granulysin is an antimicrobial and proinflammatory protein with several isoforms. While the 9 kDa isoform is a well described cytolytic molecule with pro-inflammatory activity, the functions of the 15 kDa isoform is less well understood. It was shown that 15 kDa Granulysin can act as an alarmin that is able to activate monocytes and immature dendritic cells. Granulocyte Macrophage Colony Stimulating Factor (GM-CSF) is a growth factor widely used in immunotherapy both for in vivo and ex vivo applications, especially for its proliferative effects. Many immunotherapies are based on the use of immunomodulators for the activation or suppression of the immune response These immunomodulators include cytokines, chemokines and growth factors that act on specific subsets of immune cells in vivo or ex vivo, alone or in combination, to modulate an immune response. GM-CSF is a growth factor encoded by the CSF2 gene [1] It is a glycoprotein naturally produced by lymphocytes and monocytes that induces the ex vivo proliferation of hematopoietic progenitor cells to form colonies of mature blood cells[2]. The molecular effects of GM-CSF on monocytes in vitro have not yet been completely characterized
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