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...
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2016-10-01
|
| Series: | BMC Infectious Diseases |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s12879-016-1938-8 |
| _version_ | 1811216447167266816 |
|---|---|
| author | Kristian Tonby Ida Wergeland Nora V. Lieske Dag Kvale Kjetil Tasken Anne M. Dyrhol-Riise |
| author_facet | Kristian Tonby Ida Wergeland Nora V. Lieske Dag Kvale Kjetil Tasken Anne M. Dyrhol-Riise |
| author_sort | Kristian Tonby |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-12T06:39:12Z |
| format | Article |
| id | doaj.art-94dc22755203432c8ee222b06f4ec129 |
| institution | Directory Open Access Journal |
| issn | 1471-2334 |
| language | English |
| last_indexed | 2024-04-12T06:39:12Z |
| publishDate | 2016-10-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Infectious Diseases |
| spelling | doaj.art-94dc22755203432c8ee222b06f4ec1292022-12-22T03:43:47ZengBMCBMC Infectious Diseases1471-23342016-10-0116111210.1186/s12879-016-1938-8The COX- inhibitor indomethacin reduces Th1 effector and T regulatory cells in vitro in Mycobacterium tuberculosis infectionKristian Tonby0Ida Wergeland1Nora V. Lieske2Dag Kvale3Kjetil Tasken4Anne M. Dyrhol-Riise5Institute of Clinical Medicine, University of OsloDepartment of Clinical Science, University of BergenCentre for Molecular Medicine Norway, Nordic EMBL Partnership, University of OsloInstitute of Clinical Medicine, University of OsloDepartment of Infectious Diseases, Oslo University HospitalInstitute of Clinical Medicine, University of OsloAbstract 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.http://link.springer.com/article/10.1186/s12879-016-1938-8TuberculosisCOX-inhibitorsTregsRegulatory T cellsHost-directed therapyMonocytes |
| spellingShingle | Kristian Tonby Ida Wergeland Nora V. Lieske Dag Kvale Kjetil Tasken Anne M. Dyrhol-Riise The COX- inhibitor indomethacin reduces Th1 effector and T regulatory cells in vitro in Mycobacterium tuberculosis infection BMC Infectious Diseases Tuberculosis COX-inhibitors Tregs Regulatory T cells Host-directed therapy Monocytes |
| title | The COX- inhibitor indomethacin reduces Th1 effector and T regulatory cells in vitro in Mycobacterium tuberculosis infection |
| title_full | The COX- inhibitor indomethacin reduces Th1 effector and T regulatory cells in vitro in Mycobacterium tuberculosis infection |
| title_fullStr | The COX- inhibitor indomethacin reduces Th1 effector and T regulatory cells in vitro in Mycobacterium tuberculosis infection |
| title_full_unstemmed | The COX- inhibitor indomethacin reduces Th1 effector and T regulatory cells in vitro in Mycobacterium tuberculosis infection |
| title_short | The COX- inhibitor indomethacin reduces Th1 effector and T regulatory cells in vitro in Mycobacterium tuberculosis infection |
| title_sort | cox inhibitor indomethacin reduces th1 effector and t regulatory cells in vitro in mycobacterium tuberculosis infection |
| topic | Tuberculosis COX-inhibitors Tregs Regulatory T cells Host-directed therapy Monocytes |
| url | http://link.springer.com/article/10.1186/s12879-016-1938-8 |
| work_keys_str_mv | AT kristiantonby thecoxinhibitorindomethacinreducesth1effectorandtregulatorycellsinvitroinmycobacteriumtuberculosisinfection AT idawergeland thecoxinhibitorindomethacinreducesth1effectorandtregulatorycellsinvitroinmycobacteriumtuberculosisinfection AT noravlieske thecoxinhibitorindomethacinreducesth1effectorandtregulatorycellsinvitroinmycobacteriumtuberculosisinfection AT dagkvale thecoxinhibitorindomethacinreducesth1effectorandtregulatorycellsinvitroinmycobacteriumtuberculosisinfection AT kjetiltasken thecoxinhibitorindomethacinreducesth1effectorandtregulatorycellsinvitroinmycobacteriumtuberculosisinfection AT annemdyrholriise thecoxinhibitorindomethacinreducesth1effectorandtregulatorycellsinvitroinmycobacteriumtuberculosisinfection AT kristiantonby coxinhibitorindomethacinreducesth1effectorandtregulatorycellsinvitroinmycobacteriumtuberculosisinfection AT idawergeland coxinhibitorindomethacinreducesth1effectorandtregulatorycellsinvitroinmycobacteriumtuberculosisinfection AT noravlieske coxinhibitorindomethacinreducesth1effectorandtregulatorycellsinvitroinmycobacteriumtuberculosisinfection AT dagkvale coxinhibitorindomethacinreducesth1effectorandtregulatorycellsinvitroinmycobacteriumtuberculosisinfection AT kjetiltasken coxinhibitorindomethacinreducesth1effectorandtregulatorycellsinvitroinmycobacteriumtuberculosisinfection AT annemdyrholriise coxinhibitorindomethacinreducesth1effectorandtregulatorycellsinvitroinmycobacteriumtuberculosisinfection |