title: Kynurenic acid triggers firm arrest of leukocytes to vascular endothelium under flow conditions.
abstract: Recent studies have demonstrated that kynurenic acid (KYNA), a compound produced endogenously by the interferon-gamma-induced degradation of tryptophan by indoleamine 2,3-dioxygenase, activates the previously orphaned G protein-coupled receptor, GPR35. This receptor is expressed in immune tissues, although its potential function in immunomodulation remains to be explored. We determined that GPR35 was most highly expressed on human peripheral monocytes. In an in vitro vascular flow model, KYNA triggered the firm arrest of monocytes to both fibronectin and ICAM-1, via beta(1) integrin- and beta(2) integrin-mediated mechanisms, respectively. Incubation of monocytes with pertussis toxin prior to use in flow experiments significantly reduced the KYNA-induced monocyte adhesion, suggesting that adhesion is triggered by a G(i)-mediated process. Furthermore, KYNA-triggered adhesion of monocytic cells was reduced by short hairpin RNA-mediated silencing of GPR35. Although GPR35 is expressed at slightly lower levels on neutrophils, KYNA induced firm adhesion of these cells to an ICAM-1-expressing monolayer as well. KYNA also elicited neutrophil shedding of surface L-selectin, another indicator of leukocyte activation. Taken together, these data suggest that KYNA could be an important early mediator of leukocyte recruitment.
authors.affiliation: Cardiology Division and Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Charlestown, Massachusetts 02129, USA.
authors.forename: Marita C
authors.initials: MC
authors.lastname: Barth
authors.forename: Neil
authors.initials: N
authors.lastname: Ahluwalia
authors.forename: Thomas J T
authors.initials: TJ
authors.lastname: Anderson
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Hardy
authors.forename: Sumita
authors.initials: S
authors.lastname: Sinha
authors.forename: Jose A
authors.initials: JA
authors.lastname: Alvarez-Cardona
authors.forename: Ivy E
authors.initials: IE
authors.lastname: Pruitt
authors.forename: Eugene P
authors.initials: EP
authors.lastname: Rhee
authors.forename: Richard A
authors.initials: RA
authors.lastname: Colvin
authors.forename: Robert E
authors.initials: RE
authors.lastname: Gerszten
mesh_terms: D018821:CD18 Antigens / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005353:Fibronectins / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D019012:Integrin beta1 / Q000378:metabolism; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D007736:Kynurenic Acid / Q000737:chemistry / Q000494:pharmacology*; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D015394:Molecular Structure; D034622:RNA Interference; D043562:Receptors, G-Protein-Coupled / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012212:Rheology
chemical_list: D018821:CD18 Antigens; D018691:Excitatory Amino Acid Antagonists; D005353:Fibronectins; C111379:GPR35 protein, human; D019012:Integrin beta1; D043562:Receptors, G-Protein-Coupled; D018799:Intercellular Adhesion Molecule-1; D007736:Kynurenic Acid