title: Adjuvant arthritis induces down-regulation of G protein-coupled receptor kinases in the immune system.
abstract: G protein-coupled receptors (GPCR) play a crucial role in the regulation of the immune response by, e.g., chemokines, PGs, and beta(2)-adrenergic agonists. The responsiveness of these GPCRs is turned off by the family of G protein-coupled receptor kinases (GRK1-6). These kinases act by phosphorylating the GPCR in an agonist-dependent manner, resulting in homologous desensitization of the receptor. Although GRKs are widely expressed throughout the body, leukocytes express relatively high levels of GRKs, in particular GRK2, -3, and -6. We investigated whether in vivo the inflammatory disease adjuvant arthritis (AA) induces changes in GRK expression and function in the immune system. In addition, we analyzed whether the systemic effects of AA also involve changes in GRKs in nonimmune organs. At the peak of the inflammatory process, we observed a profound down-regulation of GRK2, -3, and -6 in splenocytes and mesenteric lymph node cells from AA rats. Interestingly, no changes in GRK were observed in thymocytes and in nonimmune organs such as heart and pituitary. During the remission phase of AA, GRK levels in spleen and mesenteric lymph nodes are returning to baseline levels. The decrease in GRK2 at the peak of AA is restricted to CD45RA(+) B cells and CD4(+) T cells, and was not observed in CD8(+) T cells. In conclusion, we demonstrate in this study, for the first time, that an inflammatory process in vivo induces a tissue-specific down-regulation of GRKs in the immune system.
authors.affiliation: Department of Pediatric Immunology, Wilhelmina Children's Hospital of the University Medical Center Utrecht, Utrecht, The Netherlands. m.s.lombardi@wkz.azu.nl
authors.forename: M S
authors.initials: MS
authors.lastname: Lombardi
authors.forename: A
authors.initials: A
authors.lastname: Kavelaars
authors.forename: P M
authors.initials: PM
authors.lastname: Cobelens
authors.forename: R E
authors.initials: RE
authors.lastname: Schmidt
authors.forename: M
authors.initials: M
authors.lastname: Schedlowski
authors.forename: C J
authors.initials: CJ
authors.lastname: Heijnen
mesh_terms: D000818:Animals; D019390:Arrestins / Q000096:biosynthesis; D001169:Arthritis, Experimental / Q000201:enzymology* / Q000276:immunology* / Q000378:metabolism; D015153:Blotting, Western; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors* / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D018450:Disease Progression; D015536:Down-Regulation / Q000276:immunology*; D004789:Enzyme Activation / Q000276:immunology; D020962:Heterotrimeric GTP-Binding Proteins / Q000378:metabolism*; D007107:Immune System / Q000201:enzymology* / Q000378:metabolism; D008198:Lymph Nodes / Q000201:enzymology; D008297:Male; D008643:Mesentery; D009206:Myocardium / Q000201:enzymology; D010902:Pituitary Gland / Q000201:enzymology; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D011917:Rats, Inbred Lew; D013154:Spleen / Q000166:cytology / Q000201:enzymology; D013950:Thymus Gland / Q000166:cytology / Q000201:enzymology; D051552:beta-Adrenergic Receptor Kinases; D000071557:beta-Arrestins
chemical_list: D019390:Arrestins; D012333:RNA, Messenger; D000071557:beta-Arrestins; D017868:Cyclic AMP-Dependent Protein Kinases; D051552:beta-Adrenergic Receptor Kinases; D020962:Heterotrimeric GTP-Binding Proteins