title: mGluR1 interacts with cystic fibrosis transmembrane conductance regulator and modulates the secretion of IL-10 in cystic fibrosis peripheral lymphocytes.
abstract: 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(-4)M) 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.
authors.affiliation: Institute of Chemical Biology, Ilia State University, 3/5 Cholokashvili av., Tbilisi, Georgia.
authors.forename: L V
authors.initials: LV
authors.lastname: Shanshiashvili
authors.forename: N
authors.initials: N
authors.lastname: Dabrundashvili
authors.forename: N
authors.initials: N
authors.lastname: Natsvlishvili
authors.forename: E
authors.initials: E
authors.lastname: Kvaratskhelia
authors.forename: E
authors.initials: E
authors.lastname: Zhuravliova
authors.forename: T
authors.initials: T
authors.lastname: Barbakadze
authors.forename: S
authors.initials: S
authors.lastname: Koriauli
authors.forename: E
authors.initials: E
authors.lastname: Maisuradze
authors.forename: T
authors.initials: T
authors.lastname: Topuria
authors.forename: D G
authors.initials: DG
authors.lastname: Mikeladze
mesh_terms: D000293:Adolescent; D002462:Cell Membrane / Q000235:genetics / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D018118:Chloride Channels / Q000097:blood / Q000235:genetics; D003550:Cystic Fibrosis / Q000097:blood* / Q000235:genetics; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000097:blood* / Q000235:genetics; D015536:Down-Regulation; D005260:Female; D018698:Glutamic Acid / Q000235:genetics / Q000378:metabolism; D006801:Humans; D016753:Interleukin-10 / Q000097:blood* / Q000235:genetics; D016209:Interleukin-8 / Q000097:blood / Q000235:genetics; D008024:Ligands; D008214:Lymphocytes / Q000378:metabolism*; D008297:Male; D009154:Mutation; D010750:Phosphoproteins / Q000097:blood / Q000235:genetics; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors / Q000097:blood* / Q000235:genetics; D017923:Sodium-Hydrogen Exchangers / Q000097:blood / Q000235:genetics; D013601:T-Lymphocytes / Q000378:metabolism
chemical_list: C505032:CFTR protein, human; D018118:Chloride Channels; D016209:Interleukin-8; D008024:Ligands; D010750:Phosphoproteins; D018094:Receptors, Metabotropic Glutamate; D017923:Sodium-Hydrogen Exchangers; C104077:metabotropic glutamate receptor type 1; C093376:sodium-hydrogen exchanger regulatory factor; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D016753:Interleukin-10; D018698:Glutamic Acid