JNK1 Is required for the induction of Mkp1 expression in macrophages during proliferation and lipopolysaccharide-dependent activation.
Macrophages proliferate in the presence of their growth factor, macrophage colony-stimulating factor (M-CSF), in a process that is dependent on early and short ERK activation. Lipopolysaccharide (LPS) induces macrophage activation, stops proliferation, and delays ERK phosphorylation, thereby triggering an inflammatory response. Proliferating or activating responses are balanced by the kinetics of ERK phosphorylation, the inactivation of which correlates with Mkp1 induction. Here we show that the transcriptional induction of this phosphatase by M-CSF or LPS depends on JNK but not on the other MAPKs, ERK and p38. The lack of Mkp1 induction caused by JNK inhibition prolonged ERK-1/2 and p38 phosphorylation. The two JNK genes, jnk1 and jnk2, are constitutively expressed in macrophages. However, only the JNK1 isoform was phosphorylated and, as determined in single knock-out mice, was necessary for Mkp1 induction by M-CSF or LPS. JNK1 was also required for pro-inflammatory cytokine biosynthesis (tumor necrosis factor-alpha, interleukin-1 beta, and interleukin-6) and LPS-induced NO production. This requirement is independent of Mkp1 expression, as shown in Mkp1 knock-out mice. Our results demonstrate a critical role for JNK1 in the regulation of Mkp1 induction and in LPS-dependent macrophage activation.
Sánchez-Tilló
Ester
E
Institute for Research in Biomedicine and University of Barcelona, Barcelona Science Park, Josep Samitier 1-5, E-08028 Barcelona, Spain.
Comalada
Mónica
M
Xaus
Jordi
J
Farrera
Consol
C
Valledor
Annabel F
AF
Caelles
Carme
C
Lloberas
Jorge
J
Celada
Antonio
A
D000818:Animals; D018797:Cell Cycle Proteins / Q000096:biosynthesis*; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis; D054638:Dual Specificity Phosphatase 1; D017874:Immediate-Early Proteins / Q000096:biosynthesis*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D008262:Macrophage Activation / Q000187:drug effects / Q000502:physiology*; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D008264:Macrophages / Q000166:cytology / Q000201:enzymology*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D048055:Mitogen-Activated Protein Kinase 8 / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism; D010749:Phosphoprotein Phosphatases / Q000096:biosynthesis* / Q000172:deficiency; D054645:Protein Phosphatase 1; D017027:Protein Tyrosine Phosphatases / Q000096:biosynthesis*
D018797:Cell Cycle Proteins; D016207:Cytokines; D017874:Immediate-Early Proteins; D008070:Lipopolysaccharides; D009569:Nitric Oxide; D016173:Macrophage Colony-Stimulating Factor; D048055:Mitogen-Activated Protein Kinase 8; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1; D054638:Dual Specificity Phosphatase 1; C517020:Dusp1 protein, mouse; D017027:Protein Tyrosine Phosphatases