Toll-like receptor signaling alters the expression of regulator of G protein signaling proteins in dendritic cells: implications for G protein-coupled receptor signaling.
Conserved structural motifs on pathogens trigger pattern recognition receptors present on APCs such as dendritic cells (DCs). An important class of such receptors is the Toll-like receptors (TLRs). TLR signaling triggers a cascade of events in DCs that includes modified chemokine and cytokine production, altered chemokine receptor expression, and changes in signaling through G protein-coupled receptors (GPCRs). One mechanism by which TLR signaling could modify GPCR signaling is by altering the expression of regulator of G protein signaling (RGS) proteins. In this study, we show that human monocyte-derived DCs constitutively express significant amounts of RGS2, RGS10, RGS14, RGS18, and RGS19, and much lower levels of RGS3 and RGS13. Engagement of TLR3 or TLR4 on monocyte-derived DCs induces RGS16 and RGS20, markedly increases RGS1 expression, and potently down-regulates RGS18 and RGS14 without modifying other RGS proteins. A similar pattern of Rgs protein expression occurred in immature bone marrow-derived mouse DCs stimulated to mature via TLR4 signaling. The changes in RGS18 and RGS1 expression are likely important for DC function, because both proteins inhibit G alpha(i)- and G alpha(q)-mediated signaling and can reduce CXC chemokine ligand (CXCL)12-, CC chemokine ligand (CCL)19-, or CCL21-induced cell migration. Providing additional evidence, bone marrow-derived DCs from Rgs1(-/-) mice have a heightened migratory response to both CXCL12 and CCL19 when compared with similar DCs prepared from wild-type mice. These results indicate that the level and functional status of RGS proteins in DCs significantly impact their response to GPCR ligands such as chemokines.
Shi
Geng-Xian
GX
B Cell Molecular Immunology Section, Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Harrison
Kathleen
K
Han
Sang-Bae
SB
Moratz
Chantal
C
Kehrl
John H
JH
D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism; D016466:CHO Cells; D019556:COS Cells; D002478:Cells, Cultured; D002634:Chemotaxis, Leukocyte / Q000235:genetics / Q000276:immunology; D006224:Cricetinae; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D005260:Female; D044385:GTP-Binding Protein alpha Subunits / Q000096:biosynthesis; D006367:HeLa Cells; D006801:Humans; D008562:Membrane Glycoproteins / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000276:immunology / Q000378:metabolism; D020710:RGS Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D054398:Receptors, CCR4; D011956:Receptors, Cell Surface / Q000502:physiology*; D019707:Receptors, Chemokine / Q000378:metabolism / Q000502:physiology; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000276:immunology*; D051196:Toll-Like Receptor 3; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors
C515354:CCR4 protein, human; C515355:Ccr4 protein, mouse; D044385:GTP-Binding Protein alpha Subunits; D008562:Membrane Glycoproteins; D020710:RGS Proteins; C080831:RGS1 protein, human; C466958:RGS18 protein, human; D054398:Receptors, CCR4; D011956:Receptors, Cell Surface; D019707:Receptors, Chemokine; D043562:Receptors, G-Protein-Coupled; C495344:TLR3 protein, human; C495345:TLR4 protein, human; D051196:Toll-Like Receptor 3; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors