mGluR1 interacts with cystic fibrosis transmembrane conductance regulator and modulates the secretion of IL-10 in cystic fibrosis peripheral lymphocytes

• Published in: Molecular immunology Vol. 51; no. 3-4; pp. 310 - 315
• Main Authors: Shanshiashvili, L.V., Dabrundashvili, N., Natsvlishvili, N., Kvaratskhelia, E., Zhuravliova, E., Barbakadze, T., Koriauli, S., Maisuradze, E., Topuria, T., Mikeladze, D.G.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01-07-2012
• Subjects: Adolescent; Cell Membrane - genetics; Cell Membrane - metabolism; CFTR; Child; Child, Preschool; Chloride Channels - blood; Chloride Channels - genetics; Cystic fibrosis; Cystic Fibrosis - blood; Cystic Fibrosis - genetics; Cystic Fibrosis Transmembrane Conductance Regulator - blood; Cystic Fibrosis Transmembrane Conductance Regulator - genetics; Down-Regulation; Female; Glutamate; Glutamic Acid - genetics; Glutamic Acid - metabolism; Humans; IL-10; Interleukin-10 - blood; Interleukin-10 - genetics; Interleukin-8 - blood; Interleukin-8 - genetics; Ligands; Lymphocytes - metabolism; Male; Mutation; Phosphoproteins - blood; Phosphoproteins - genetics; Receptors, Metabotropic Glutamate - antagonists & inhibitors; Receptors, Metabotropic Glutamate - blood; Receptors, Metabotropic Glutamate - genetics; Sodium-Hydrogen Exchangers - blood; Sodium-Hydrogen Exchangers - genetics; T-Lymphocytes - metabolism; Cystic fibrosis; Glutamate; IL-10; CFTR
• ISSN: 0161-5890; 1872-9142
• DOI: 10.1016/j.molimm.2012.03.029

► Production of IL-10 in normal lymphocytes is controlled by mGluR1. ► Diminished expression of mGluR1 in CF disarranges the secretion of IL-10. ► Macromolecular complex between mGluR1 and CFTR is impaired in CF lymphocytes. ► Competition for CAL between CFTR and mGluR1 down-regulates the trafficking of mGluR1a.
Cystic fibrosis (CF) is caused by the mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel. CFTR dysfunction in T cells could lead directly to aberrant immune responses. The action of glutamate on the secretion of IL-8 and IL-10 by lymphocytes derived from healthy subjects and cystic CF patients, as well as the expression of metabotropic glutamate receptor subtype 1 (mGluR1) in the membrane fractions of lymphocytes was investigated. Our results have shown that CF-derived T-cells in the presence of IL-2 produce more IL-8 and IL-10, than T-cell from healthy control. However, only in normal lymphocytes a significant increase (144%) in the IL-10 secretion during exposure to high concentration of glutamate (10−4M) was detected. Glutamate-dependent secretion of IL-10 was not inhibited either by NMDA-receptor (NMDAR), or by AMPA-receptor (AMPAR) antagonist. Only mGluR1 antagonist, LY367385, strongly decreases the production of IL-10. Furthermore, the content of mGluR1, as well as cystic fibrosis transmembrane conductance regulator-associated ligand (CAL), Na+/H+ exchanger regulatory factor 1 (NHERF-1), was analyzed in plasma membrane of lymphocytes after immunoprecipitation of CFTR. We have found that normal, non-mutated CFTR, as well as mutated forms of CFTR were associated with metabotropic mGluR1, but the level of surface exposed mGluR1 in CF-lymphocytes was much lower than in normal cells. Besides, our results have shown that normal, non-mutated CFTR, as well as mutated forms of CFTR were associated with NHERF-1 and CAL; however in lymphocytes with CFTR mutation the amount of cell-surface expressed CFTR-CAL complex was greatly decreased. We have concluded that CFTR and mGluR1 could compete for binding to CAL, which in turn downregulates the post-synthetic trafficking of mGluR1 and decreases the synthesis of IL-10.