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

  • Front Cell Infect Microbiol. 2021 Jul 9;11:669623. doi: 10.3389/fcimb.2021.669623.
Marthe Jøntvedt Jørgensen  1  2 ,  Kristin G Nore  1 ,  Hans Christian D Aass  3 ,  Emilie Layre  4 ,  Jérôme Nigou  4 ,  Rasmus Mortensen  5 ,  Kjetil Tasken  1  6 ,  Dag Kvale  1 ,  Synne Jenum  2 ,  Kristian Tonby  1  2 ,  Anne Ma Dyrhol-Riise  1  2
Affiliations
  • 1. Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
  • 2. Department of Infectious Diseases, Oslo University Hospital, Oslo, Norway.
  • 3. Department of Medical Biochemistry, Oslo University Hospital, Oslo, Norway.
  • 4. Institut de Pharmacologie et de Biologie Structurale, Université de Toulouse, CNRS, Université Paul Sabatier, Toulouse, France.
  • 5. Department of Infectious Disease Immunology, Statens Serum Institut, Copenhagen, Denmark.
  • 6. Deparment of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.
PMID: 34307194 DOI: 10.3389/fcimb.2021.669623
Abstract

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.

Keywords
cyclooxygenase-2 inhibitor; cytokines; eicosanoids; host-directed therapy (HDT); innate immunity; lipooxygenase; monocytes; tuberculosis.
Products