TY - JOUR
T1 - Pivotal Advance: Arginase-1-independent polyamine production stimulates the expression of IL-4-induced alternatively activated macrophage markers while inhibiting LPS-induced expression of inflammatory genes
AU - van den Bossche, J.
AU - Lamers, W.H.
AU - Köhler, E.S.
AU - Geuns, J.M.
AU - Alhonen, L.
AU - Uimari, A.
AU - Pirnes-Karhu, S.
AU - Van Overmeire, E.
AU - Morias, Y.
AU - Brys, L.
AU - Vereecke, L.
AU - De Baetselier, P.
AU - Van Ginderachter, J.A.
PY - 2012/5
Y1 - 2012/5
N2 - In macrophages, basal polyamine (putrescine, spermidine, and spermine) levels are relatively low but are increased upon IL-4 stimulation. This Th2 cytokine induces Arg1 activity, which converts arginine into ornithine, and ornithine can be decarboxylated by ODC to produce putrescine, which is further converted into spermidine and spermine. Recently, we proposed polyamines as novel agents in IL-4-dependent E-cadherin regulation in AAMs. Here, we demonstrate for the first time that several, but not all, AAM markers depend on polyamines for their IL-4-induced gene and protein expression and that polyamine dependency of genes relies on the macrophage type. Remarkably, Arg1-deficient macrophages display rather enhanced IL-4-induced polyamine production, suggesting that an Arg1-independent polyamine synthesis pathway may operate in macrophages. On the other side of the macrophage activation spectrum, LPS-induced expression of several proinflammatory genes was increased significantly in polyamine-depleted CAMs. Overall, we propose Arg1 independently produced polyamines as novel regulators of the inflammatory status of the macrophage. Indeed, whereas polyamines are needed for IL-4-induced expression of several AAM mediators, they inhibit the LPS-mediated expression of proinflammatory genes in CAMs.
AB - In macrophages, basal polyamine (putrescine, spermidine, and spermine) levels are relatively low but are increased upon IL-4 stimulation. This Th2 cytokine induces Arg1 activity, which converts arginine into ornithine, and ornithine can be decarboxylated by ODC to produce putrescine, which is further converted into spermidine and spermine. Recently, we proposed polyamines as novel agents in IL-4-dependent E-cadherin regulation in AAMs. Here, we demonstrate for the first time that several, but not all, AAM markers depend on polyamines for their IL-4-induced gene and protein expression and that polyamine dependency of genes relies on the macrophage type. Remarkably, Arg1-deficient macrophages display rather enhanced IL-4-induced polyamine production, suggesting that an Arg1-independent polyamine synthesis pathway may operate in macrophages. On the other side of the macrophage activation spectrum, LPS-induced expression of several proinflammatory genes was increased significantly in polyamine-depleted CAMs. Overall, we propose Arg1 independently produced polyamines as novel regulators of the inflammatory status of the macrophage. Indeed, whereas polyamines are needed for IL-4-induced expression of several AAM mediators, they inhibit the LPS-mediated expression of proinflammatory genes in CAMs.
KW - AAM
KW - M2
KW - classically activated macrophage (CAM or M1)
KW - IL-4-regulated genes
KW - LPS-regulated genes
KW - NITRIC-OXIDE SYNTHASE
KW - OVEREXPRESSING SPERMIDINE/SPERMINE N-1-ACETYLTRANSFERASE
KW - PERFORMANCE LIQUID-CHROMATOGRAPHY
KW - ORNITHINE-DECARBOXYLASE
KW - TRANSGENIC MICE
KW - IN-VIVO
KW - DIFFERENTIAL EXPRESSION
KW - ARGININE METABOLISM
KW - ANTIZYME INHIBITOR
KW - INTERFERON-GAMMA
U2 - 10.1189/jlb.0911453
DO - 10.1189/jlb.0911453
M3 - Article
C2 - 22416259
SN - 0741-5400
VL - 91
SP - 685
EP - 699
JO - Journal of Leukocyte Biology
JF - Journal of Leukocyte Biology
IS - 5
ER -