Toll-like receptor signaling alters the expression of regulator of g protein signaling proteins in dendritic cells: implications for g protein-coupled receptor signaling

Shi GX, Harrison K, Han SB, Moratz C and Kehrl JH
Source: J Immunol
Publication Date: (2004)
Issue: 172(9): 5175-5184
Research Area:
Immunotherapy / Hematology
Cells used in publication:
Dendritic cell (NHDC), human
Species: human
Tissue Origin: blood
Primary human monocyte derived dendritic cells were nucleofected with GFP tagged sequences of hRGS18, hRGS13 and hRGS1. A comparison of the effect of hRGS13 and hRGS18 protein, using a cell migration assay, revealed an inhibiting effect of the hRSG18 protein on dendritic cell migration.
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.