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Neutrophil migration towards C5a and CXCL8 is prevented by non-steroidal anti-inflammatory drugs via inhibition of different pathways

Publié dansBritish journal of pharmacology, vol. 171, no. 14, p. 3376-3393
Date de publication2014
Résumé

BACKGROUND AND PURPOSE:Non-steroidal anti-inflammatory drugs (NSAIDs) have been shown to induce PG-independent anti-inflammatory actions. Here, we investigated the role of three different NSAIDs (naproxen, ibuprofen and oxaprozin) on neutrophil responses to CXCL8 and C5a. EXPERIMENTAL APPROACH:Human neutrophils were isolated from healthy volunteers by dextran and Ficoll-Hypaque density gradients. Neutrophils were pre-incubated with different concentrations (1-100 µM) of NSAIDs or kinase inhibitors. Neutrophil degranulation into supernatants was tested by elisa and zymography. Neutrophil chemotaxis was determined using Boyden chambers. F-actin polymerization was determined by Alexa-Fluor 488-conjugated phalloidin fluorescent assay. Integrin expression was assessed by flow cytometry. The phosphorylation of intracellular kinases was studied by Western blot. KEY RESULTS:Pretreatment with NSAIDs did not affect neutrophil degranulation, but inhibited neutrophil migration and polymerization of F-actin, in response to CXCL8 and C5a. Pretreatment with different NSAIDs prevented C5a-induced integrin (CD11b) up-regulation, while only ibuprofen reduced CXCL8-induced CD11b up-regulation. Pre-incubation with naproxen or oxaprozin, but not ibuprofen, inhibited the PI3K/Akt-dependent chemotactic pathways. Both endogenous (released in cell supernatants) or exogenous (added to cell cultures) PGE2 did not affect C5a- or CXCL8-induced activities. Short-term incubation with NSAIDs did not affect neutrophil PGE2 release. CONCLUSION AND IMPLICATIONS:Treatment with NSAIDs reduced C5a- and CXCL8-induced neutrophil migration and F-actin polymerization via different mechanisms. Inhibition by ibuprofen was associated with integrin down-regulation, while naproxen and oxaprozin blocked the PI3K/Akt pathway. Both NSAID actions were independent of COX inhibition and PGE2 release.

Mots-clés
  • Adult
  • Anti-Inflammatory Agents, Non-Steroidal/pharmacology
  • Chemotaxis, Leukocyte/drug effects
  • Complement C5a/metabolism
  • Dose-Response Relationship, Drug
  • Healthy Volunteers
  • Humans
  • Interleukin-8/metabolism
  • Middle Aged
  • Neutrophils/cytology/drug effects/metabolism
  • Phosphatidylinositol 3-Kinases/antagonists & inhibitors/metabolism
  • Proto-Oncogene Proteins c-akt/antagonists & inhibitors/metabolism
  • Structure-Activity Relationship
  • Young Adult
Citation (format ISO)
BERTOLOTTO, Maria et al. Neutrophil migration towards C5a and CXCL8 is prevented by non-steroidal anti-inflammatory drugs via inhibition of different pathways. In: British journal of pharmacology, 2014, vol. 171, n° 14, p. 3376–3393. doi: 10.1111/bph.12670
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Article (Published version)
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Identifiants
ISSN du journal0007-1188
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Création14/10/2015 14:51:00
Première validation14/10/2015 14:51:00
Heure de mise à jour14/03/2023 23:55:07
Changement de statut14/03/2023 23:55:07
Dernière indexation16/01/2024 19:42:18
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