Proteinase-activated receptor 2 activation promotes an anti-inflammatory and alternatively activated phenotype in LPS-stimulated murine macrophages.
Proteinase-activated receptor 2 (PAR(2)), a 7-transmembrane G protein-coupled receptor, contributes to inflammation either positively or negatively in different experimental systems. Previously, we reported that concurrent activation of PAR(2) and TLRs in human lung and colonic epithelial cells resulted in a synergistic increase in NF-κB-mediated gene expression, but a down-regulation of IRF-3-mediated gene expression. In this study, the effect of PAR(2) activation on LPS-induced TLR4 signaling was examined in primary murine macrophages. The PAR(2) activation of wild-type macrophages enhanced LPS-induced expression of the anti-inflammatory cytokine, IL-10, while suppressing gene expression of pro-inflammatory cytokines, TNF-α, IL-6, and IL-12. Similar PAR(2)-mediated effects on LPS-stimulated IL-10 and IL-12 mRNA were also observed in vivo. In contrast, PAR 2-/- macrophages exhibited diminished LPS-induced IL-10 mRNA and protein expression and downstream STAT3 activation, but increased KC mRNA and protein. PAR(2) activation also enhanced both rIL-4- and LPS-induced secretion of IL-4 and IL-13, and mRNA expression of alternatively activated macrophage (AA-M) markers, e.g. arginase-1, mannose receptor, Ym-1. Thus, in the context of a potent inflammatory stimulus like LPS, PAR(2) activation acts to re-establish tissue homeostasis by dampening the production of inflammatory mediators and causing the differentiation of macrophages that may contribute to the development of a Th2 response.
Department of Microbiology and Immunology, University of Maryland, Baltimore (UMB), School of Medicine, Baltimore, Maryland, USA.
Quan M
QM
Nhu
Kari Ann
KA
Shirey
Meghan E
ME
Pennini
Jennifer
J
Stiltz
Stefanie N
SN
Vogel
D000818:Animals; D015153:Blotting, Western; D016207:Cytokines / Q000096:biosynthesis; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D015870:Gene Expression / Q000187:drug effects; D007202:Indicators and Reagents; D018836:Inflammation Mediators / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008262:Macrophage Activation / Q000187:drug effects*; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D060888:Real-Time Polymerase Chain Reaction; D044464:Receptor, PAR-2 / Q000187:drug effects / Q000502:physiology*; D013268:Stimulation, Chemical; D046509:Tissue Culture Techniques; D051197:Toll-Like Receptor 4 / Q000187:drug effects
D016207:Cytokines; D007202:Indicators and Reagents; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D044464:Receptor, PAR-2; D051197:Toll-Like Receptor 4
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