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

Kristian Tonby,Anne M Dyrhol-Riise,Nora V Lieske,Ida Wergeland,Kjetil Tasken,Dag Kvale

doi:10.1186/s12879-016-1938-8

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.

Highlights

Tuberculosis (TB) causes a major burden on global health with long and cumbersome TB treatment regimens
Indomethacin reduces up-regulation of Mycobacterium tuberculosis (Mtb) antigen induced FOXP3+CD25++ T regulatory cells (Tregs) We assessed the in vitro effects of the COX- inhibitors (COX-i) indomethacin on Tregs from patients with active TB disease prior to initiation of anti-TB chemotherapy (Fig. 3)
We observed a significant up-regulation both in the fraction and the median fluorescence intensity (MFI) of FOXP3+CD25++ Tregs in the ESAT-6 and Ag85 stimulated CD4+ T cells with a significant reduction in the samples treated with indomethacin both for the fraction of FOXP3+CD25++ Tregs (ESAT6; p = 0.004 and Ag85; p < 0.001) (Fig. 3a) and FOXP3 MFI (Fig. 3b)

Summary

Introduction

Tuberculosis (TB) causes a major burden on global health with long and cumbersome TB treatment regimens. Host-directed therapies (HDTs) in conjunction with standard anti-TB drug regimens may reduce the duration of therapy, achieve better treatment outcomes, lower the risk of developing further drug resistance and decrease the chances of relapse or reinfection [2, 3]. In chronic infections such as TB, immune-mediated tissue injury may become more detrimental than the pathogen itself and the immune system have evolved mechanisms to balance pro and anti-inflammatory signals [4]. Targeting of Tregs may have potential as host directed adjunctive therapies [9]

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