Plasma LOX-Products and Monocyte Signaling Is Reduced by Adjunctive Cyclooxygenase-2 Inhibitor in a Phase I Clinical Trial of Tuberculosis Patients - Archive ouverte HAL Accéder directement au contenu
Article Dans Une Revue Frontiers in Cellular and Infection Microbiology Année : 2021

Plasma LOX-Products and Monocyte Signaling Is Reduced by Adjunctive Cyclooxygenase-2 Inhibitor in a Phase I Clinical Trial of Tuberculosis Patients

Kristin Nore
  • Fonction : Auteur
Hans Christian D. Aass
  • Fonction : Auteur
Rasmus Mortensen
  • Fonction : Auteur
Kjetil Tasken
  • Fonction : Auteur
Dag Kvale
  • Fonction : Auteur
Synne Jenum
  • Fonction : Auteur

Résumé

Introduction Eicosanoids and intracellular signaling pathways are potential targets for host-directed therapy (HDT) in tuberculosis (TB). We have explored the effect of cyclooxygenase 2 inhibitor (COX-2i) treatment on eicosanoid levels and signaling pathways in monocytes. Methods Peripheral blood mononuclear cells isolated from TB patients included in a randomized phase I clinical trial of standard TB treatment with (n=21) or without (n=18) adjunctive COX-2i (etoricoxib) were analyzed at baseline, day 14 and day 56. Plasma eicosanoids were analyzed by ELISA and liquid chromatography-mass spectrometry (LC-MS), plasma cytokines by multiplex, and monocyte signaling by phospho-flow with a defined set of phospho-specific antibodies. Results Lipoxygenase (LOX)-derived products (LXA4 and 12-HETE) and pro-inflammatory cytokines were associated with TB disease severity and were reduced during TB therapy, possibly accelerated by adjunctive COX-2i. Phosphorylation of p38 MAPK, NFkB, Erk1/2, and Akt in monocytes as well as plasma levels of MIG/CXCL9 and procalcitonin were reduced in the COX-2i group compared to controls. Conclusion COX-2i may reduce excess inflammation in TB via the LOX-pathway in addition to modulation of phosphorylation patterns in monocytes. Immunomodulatory effects of adjunctive COX-2i in TB should be further investigated before recommended for use as a HDT strategy.
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hal-03445397 , version 1 (23-11-2021)

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Marthe Jøntvedt Jørgensen, Kristin Nore, Hans Christian D. Aass, Emilie Layre, Jérôme Nigou, et al.. Plasma LOX-Products and Monocyte Signaling Is Reduced by Adjunctive Cyclooxygenase-2 Inhibitor in a Phase I Clinical Trial of Tuberculosis Patients. Frontiers in Cellular and Infection Microbiology, 2021, 11, pp.669623. ⟨10.3389/fcimb.2021.669623⟩. ⟨hal-03445397⟩
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