Actions of translocator protein ligands on neutrophil adhesion and motility induced by G-protein coupled receptor signaling.
The 18 kDa translocator protein (TSPO) also known as the peripheral benzodiazepine receptor (PBR), mediates the transportation of cholesterol and anions from the outer to the inner mitochondrial membrane in different cells types. Although recent evidences indicate a potential role for TSPO in the development of inflammatory processes, the mechanisms involved have not been elucidated. The present study investigated the ability of the specific TSPO ligands, the isoquinoline carboxamide PK11195 and benzodiazepine Ro5-4864, on neutrophil recruitment promoted by the N-formylmethionyl-leucyl-phenylalanine peptide (fMLP), an agonist of G-protein coupled receptor (GPCR). Pre-treatment with Ro5-4864 abrograted fMLP-induced leukocyte-endothelial interactions in mesenteric postcapillary venules in vivo. Moreover, in vitro Ro5-4864 treatment prevented fMLP-induced: (i) L-selectin shedding and overexpression of PECAM-1 on the neutrophil cell surface; (ii) neutrophil chemotaxis and (iii) enhancement of intracellular calcium cations (iCa(+2)). Intriguingly, the two latter effects were augmented by cell treatment with PK11195. An allosteric agonist/antagonist relation may be suggested, as the effects of Ro5-4864 on fMLP-stimulated neutrophils were reverted by simultaneous treatment with PK11195. Taken together, these data highlight TSPO as a modulator of pathways of neutrophil adhesion and locomotion induced by GPCR, connecting TSPO actions and the onset of an innate inflammatory response.
Department of Clinical and Toxicological Analyses, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil.
Camila Bento
CB
de Lima
Eduardo K
EK
Tamura
Trindad
T
Montero-Melendez
João
J
Palermo-Neto
Mauro
M
Perretti
Regina P
RP
Markus
Sandra Helena Poliselli
SH
Farsky
D000818:Animals; D001570:Benzodiazepinones / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D002352:Carrier Proteins / Q000819:agonists*; D002448:Cell Adhesion / Q000187:drug effects; D002450:Cell Communication / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D002633:Chemotaxis / Q000187:drug effects* / Q000502:physiology; D004727:Endothelium / Q000502:physiology; D007546:Isoquinolines / Q000494:pharmacology*; D019041:L-Selectin / Q000378:metabolism; D008024:Ligands; D008297:Male; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D009504:Neutrophils / Q000187:drug effects* / Q000502:physiology; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D043562:Receptors, G-Protein-Coupled / Q000819:agonists*; D011963:Receptors, GABA-A; D015398:Signal Transduction
D001570:Benzodiazepinones; D002352:Carrier Proteins; D007546:Isoquinolines; D008024:Ligands; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D043562:Receptors, G-Protein-Coupled; D011963:Receptors, GABA-A; D019041:L-Selectin; C069997:Tspo protein, rat; C028513:4'-chlorodiazepam; D009240:N-Formylmethionine Leucyl-Phenylalanine; D002118:Calcium; C037850:PK 11195