title: The COX- inhibitor indomethacin reduces Th1 effector and T regulatory cells in vitro in Mycobacterium tuberculosis infection.
abstract: BACKGROUND
  Tuberculosis (TB) causes a major burden on global health with long and cumbersome TB treatment regimens. Host-directed immune modulating therapies have been suggested as adjunctive treatment to TB antibiotics. Upregulated cyclooxygenase-2 (COX-2)-prostaglandin E2 (PGE2) signaling pathway may cause a dysfunctional immune response that favors survival and replication of Mycobacterium tuberculosis (Mtb).
  
  
  METHODS
  Blood samples were obtained from patients with latent TB (n = 9) and active TB (n = 33) before initiation of anti-TB chemotherapy. COX-2 expression in monocytes and ESAT-6 and Ag85 specific T cell cytokine responses (TNF-α, IFN-γ, IL-2), proliferation (carboxyfluorescein succinimidyl ester staining) and regulation (FOXP3+ T regulatory cells) were analysed by flow cytometry and the in vitro effects of the COX-1/2 inhibitor indomethacin were measured.
  
  
  RESULTS
  We demonstrate that indomethacin significantly down-regulates the fraction of Mtb specific FOXP3+ T regulatory cells (ESAT-6; p = 0.004 and Ag85; p < 0.001) with a concomitant reduction of Mtb specific cytokine responses and T cell proliferation in active TB. Although active TB tend to have higher levels, there are no significant differences in COX-2 expression between unstimulated monocytes from patients with active TB compared to latent infection. Monocytes in both TB groups respond with a significant upregulation of COX-2 after in vitro stimulation.
  
  
  CONCLUSIONS
  Taken together, our in vitro data indicate a modulation of the Th1 effector and T regulatory cells in Mtb infection in response to the COX-1/2 inhibitor indomethacin. The potential role as adjunctive host-directed therapy in TB disease should be further evaluated in both animal studies and in human clinical trials.
authors: Institute of Clinical Medicine, University of Oslo, Oslo, Norway. kristian.tonby@medisin.uio.no.|Department of Infectious Diseases, Oslo University Hospital, Oslo, Norway. kristian.tonby@medisin.uio.no.
authors: Kristian
authors: K
authors: Tonby
authors: Department of Clinical Science, University of Bergen, Bergen, Norway.
authors: Ida
authors: I
authors: Wergeland
authors: Centre for Molecular Medicine Norway, Nordic EMBL Partnership, University of Oslo, Oslo, Norway.
authors: Nora V
authors: NV
authors: Lieske
authors: Institute of Clinical Medicine, University of Oslo, Oslo, Norway.|Department of Infectious Diseases, Oslo University Hospital, Oslo, Norway.|K.G. Jebsen Inflammation Research Centre, University of Oslo, Oslo, Norway.
authors: Dag
authors: D
authors: Kvale
authors: Department of Infectious Diseases, Oslo University Hospital, Oslo, Norway.|Centre for Molecular Medicine Norway, Nordic EMBL Partnership, University of Oslo, Oslo, Norway.|K.G. Jebsen Inflammation Research Centre, University of Oslo, Oslo, Norway.|Biotechnology Centre, University of Oslo, Oslo, Norway.
authors: Kjetil
authors: K
authors: Tasken
authors: Institute of Clinical Medicine, University of Oslo, Oslo, Norway.|Department of Infectious Diseases, Oslo University Hospital, Oslo, Norway.|Department of Clinical Science, University of Bergen, Bergen, Norway.|K.G. Jebsen Inflammation Research Centre, University of Oslo, Oslo, Norway.
authors: Anne M
authors: AM
authors: Dyrhol-Riise
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000942:Antigens, Bacterial / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000097:blood; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D016207:Cytokines / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology*; D055985:Latent Tuberculosis / Q000188:drug therapy / Q000382:microbiology / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000472:pathogenicity; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000382:microbiology; D018417:Th1 Cells / Q000187:drug effects; D014376:Tuberculosis / Q000188:drug therapy* / Q000382:microbiology / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D055815:Young Adult
chemical_list: D000942:Antigens, Bacterial; D016861:Cyclooxygenase Inhibitors; D016207:Cytokines; D014409:Tumor Necrosis Factor-alpha; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D007213:Indomethacin
keywords: COX-inhibitors; Cytokines; Host-directed therapy; Monocytes; Regulatory T cells; Tregs; Tuberculosis