Dynamic regulation of pro- and anti-inflammatory cytokines by MAPK phosphatase 1 (MKP-1) in innate immune responses.
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.
Chi
Hongbo
H
Section of Immunobiology, Department of Pharmacology, and Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06520, USA.
Barry
Sean P
SP
Roth
Rachel J
RJ
Wu
J Julie
JJ
Jones
Elizabeth A
EA
Bennett
Anton M
AM
Flavell
Richard A
RA
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D033942:Adaptor Proteins, Vesicular Transport / Q000378:metabolism; D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D016207:Cytokines / Q000096:biosynthesis*; D054638:Dual Specificity Phosphatase 1; D017874:Immediate-Early Proteins / Q000235:genetics / Q000378:metabolism*; D007113:Immunity, Innate / Q000235:genetics; D016753:Interleukin-10 / Q000096:biosynthesis; D015850:Interleukin-6 / Q000096:biosynthesis; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology; D051379:Mice; D008817:Mice, Mutant Strains; D053594:Myeloid Differentiation Factor 88; D010749:Phosphoprotein Phosphatases / Q000235:genetics / Q000378:metabolism*; D054645:Protein Phosphatase 1; D017027:Protein Tyrosine Phosphatases / Q000235:genetics / Q000378:metabolism*; D012772:Shock, Septic / Q000235:genetics / Q000276:immunology*; D051193:Toll-Like Receptors / Q000819:agonists / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D018797:Cell Cycle Proteins; D016207:Cytokines; D054638:Dual Specificity Phosphatase 1; D017874:Immediate-Early Proteins; D016753:Interleukin-10; D015850:Interleukin-6; D048031:JNK Mitogen-Activated Protein Kinases; D008070:Lipopolysaccharides; D053594:Myeloid Differentiation Factor 88; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1; D017027:Protein Tyrosine Phosphatases; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha; D048051:p38 Mitogen-Activated Protein Kinases; C507780:Myd88 protein, mouse; C476286:Ticam1 protein, mouse; C517020:Dusp1 protein, mouse