Proc Natl Acad Sci U S A 2006,
PMID: 16461893
Chi, Hongbo; Barry, Sean P; Roth, Rachel J; Wu, J Julie; Jones, Elizabeth A; Bennett, Anton M; Flavell, Richard A
Engagement of Toll-like receptors (TLRs) on macrophages leads to activation of the mitogen-activated protein kinases (MAPKs), which contribute to innate immune responses. MAPK activity is regulated negatively by MAPK phosphatases (MKPs). MKP-1, the founding member of this family of dual-specificity phosphatases, has been implicated in regulating lipopolysaccharide (LPS) responses, but its role in TLR-mediated immune responses in vivo has not been defined. Here, we show that mice deficient in MKP-1 were highly susceptible to endotoxic shock in vivo, associated with enhanced production of proinflammatory cytokines TNF-alpha and IL-6 and an anti-inflammatory cytokine, IL-10. We further examined the regulation and function of MKP-1 in macrophages, a major cell type involved in endotoxic shock. MKP-1 was transiently induced by TLR stimulation through pathways mediated by both myeloid differentiation factor 88 (MyD88) and TIR domain-containing adaptor inducing IFN-beta (TRIF). MKP-1 deficiency led to sustained activation of p38 MAPK and c-Jun N-terminal kinase (JNK) in LPS-treated macrophages. In response to TLR signals, MKP-1-deficient macrophages produced 5- to 10-fold higher IL-10, which could be blocked by a p38 MAPK inhibitor. Thus, p38 MAPK plays a critical role in mediating IL-10 synthesis in TLR signaling. TNF-alpha was found to be more abundant in MKP-1-deficient macrophages within 2 hours of TLR stimulation, but its production was rapidly down-regulated by IL-10. Our studies demonstrate that MKP-1 attenuates the activities of p38 MAPK and JNK to regulate both pro- and anti-inflammatory cytokines in TLR signaling. These results highlight the complex mechanisms by which the MAPKs regulate innate immunity.
Diseases/Pathways annotated by Medline MESH: Shock, Septic
Document information provided by NCBI PubMed
Text Mining Data
MAPK ⊣ MKP-1: "
MKP-1 deficiency
led to sustained activation of p38
MAPK and c-Jun N-terminal kinase (JNK) in LPS treated macrophages
"
c-Jun N-terminal kinase (JNK) ⊣ MKP-1: "
MKP-1 deficiency led to sustained activation of p38 MAPK and c-Jun N-terminal kinase (JNK) in LPS treated macrophages
"
IL-10 → TLR: "
In response to TLR signals, MKP-1-deficient macrophages produced 5- to 10-fold higher IL-10 , which could be blocked by a p38 MAPK inhibitor
"
IL-10 → p38: "
In response to TLR signals, MKP-1-deficient macrophages produced 5- to 10-fold higher IL-10 , which could be blocked by a p38 MAPK inhibitor
"
IL-10 → MAPK: "
In response to TLR signals, MKP-1-deficient macrophages produced 5- to 10-fold higher IL-10 , which could be blocked by a p38 MAPK inhibitor
"
TLR — MAPK: "
Thus, p38 MAPK plays a critical role in mediating IL-10 synthesis in TLR signaling
"
IL-10 — MAPK: "
Thus, p38 MAPK plays a critical role in mediating IL-10 synthesis in TLR signaling
"
TNF-alpha ⊣ IL-10: "
TNF-alpha was found to be more abundant in MKP-1-deficient macrophages within 2 hours of TLR stimulation, but its production was rapidly down-regulated by IL-10
"
Manually curated Databases
-
NCI Pathway Database Regulation of p38-alpha and p38-beta:
p38alpha-beta-active (MAPK14/MAPK11)
→
p38alpha-beta/MKP1 complex (MAPK14_MAPK11-DUSP1)
(modification, collaborate)
Evidence: mutant phenotype, physical interaction, other species
-
NCI Pathway Database Regulation of p38-alpha and p38-beta:
p38alpha-beta-active (MAPK14/MAPK11)
→
MKP1 (DUSP1)
(modification, collaborate)
Evidence: mutant phenotype, physical interaction, other species
-
NCI Pathway Database Regulation of p38-alpha and p38-beta:
p38alpha-beta/MKP1 complex (MAPK14_MAPK11-DUSP1)
→
MKP1 (DUSP1)
(modification, collaborate)
Evidence: mutant phenotype, physical interaction, other species
In total, 6 gene pairs are associated to this article in curated databases