The COX- inhibitor indomethacin reduces Th1 effector and T regulatory cells in vitro in Mycobacterium tuberculosis infection

Abstract

BackgroundTuberculosis (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).MethodsBlood 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.ResultsWe 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.ConclusionsTaken 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.

Tuberculosis: progress and advances in development of new drugs, treatment regimens, and host-directed therapies

“…Selective COX-2 inhibitors decrease unproductive inflammation and improve survival in murine TB by direct anti-mycobacterial activity. [101][102] COX2-inhibition is however, also associated with cell necrosis, which favours Mtb survival. 103 Zileuton, a 5-LOX inhibitor, approved for use in asthma, increases PGE2 and inhibits leukotrienes to limit type I IFN-mediated lung pathology.…”

Adjunctive use of celecoxib with anti-tuberculosis drugs: evaluation in a whole-blood bactericidal activity model

“…We also hypothesised that celecoxib might affect growth in the WBA assay through the direct T-cell immunomodulatory effects of COX inhibition 15 . The ex vivo WBA paradigm has the potential advantage over in vitro assays of evaluating the integration of effects of anti-mycobacterial drugs with host immune responses, both of which have been established independently in healthy volunteers using the WBA model 19 , 22 , 26 .…”

“…Dosing TB-infected murine models with COX inhibitors reduces lung infiltrates, lowers bacillary loads and improves survival 7 , 11 – 14 . COX suppression also inhibits immune activation of T cells by Mycobacterium tuberculosis (Mtb) 15 . In addition, synergy between anti-tuberculosis drugs and COX inhibition (pyrazinamide with ibuprofen 16 and streptomycin with diclofenac 12 ) has been seen in mouse models.…”

Immunosuppressive role of PGE2 during human tuberculosis

“…Strikingly, Tonby et al reported that the use of this inhibitor decreases the proliferation and cytokine secretion of mycobacterial antigen stimulated lymphocytes from TB patients. However, these observations could be linked to a direct inhibitory effect of indomethacin on the activation of the NF-κB pathway 21 .…”