Abstract
Protective immune responses to Mycobacterium tuberculosis (Mtb) infection substantially depend on a delicate balance within cytokine networks. Thus, immunosuppressive therapy by cytokine blockers, as successfully used in the management of various chronic inflammatory diseases, is often connected with an increased risk for tuberculosis (TB) reactivation. Hence, identification of alternative therapeutics which allow the treatment of inflammatory diseases without compromising anti-mycobacterial immunity remains an important issue. On the other hand, in the context of novel therapeutic approaches for the management of TB, host-directed adjunct therapies, which combine administration of antibiotics with immunomodulatory drugs, play an increasingly important role, particularly to reduce the duration of treatment. In both respects, cytokines/cytokine receptors related to the common receptor subunit gp130 may serve as promising target candidates. Within the gp130 cytokine family, interleukin (IL)-6, IL-11 and IL-27 are most explored in the context of TB. This review summarizes the differential roles of these cytokines in protection and immunopathology during Mtb infection and discusses potential therapeutic implementations with respect to the aforementioned approaches.
Highlights
Tuberculosis (TB) is still the leading cause of death from an infectious agent and represents a major health problem, with one quarter of the global population infected with Mycobacterium tuberculosis (Mtb) [1]
Cells in T helper 1 (TH1) immune responses and during the development of TH17 cells, IL-6 can act in an anti-inflammatory fashion through the membrane-bound IL-6Rα chain (mIL-6Rα) on macrophages because IL-6 cis-signaling inhibits the release of pro-inflammatory cytokines such as IL-12 and IL-23 by activated macrophages in vitro [82,83]
IL-6 binds to a soluble IL-6Rα chain that is secreted after proteolytic cleavage of mIL-6Rα by the metalloprotease ADAM17 in a process called shedding [85,86] (Figure 2)
Summary
Tuberculosis (TB) is still the leading cause of death from an infectious agent and represents a major health problem, with one quarter of the global population infected with Mycobacterium tuberculosis (Mtb) [1]. Because containment of Mtb in these individuals is facilitated by an active immune response, anti-inflammatory therapies to treat autoimmune and chronic inflammatory diseases such as rheumatoid arthritis, psoriasis and Crohn’s disease increase the risk of reactivation of latent. In order to develop novel immunomodulatory interventions (1) for the anti-inflammatory therapy of potentially latently Mtb-infected patients suffering from autoimmune or chronic inflammatory diseases or (2) for the adjunct treatment of TB, the understanding of the mechanisms that mediate protection and pathogenesis in TB is mandatory. Because TH1 and TH17 cells are both strong inducers of inflammatory immune responses, both contribute to chronic inflammation and tissue destruction in experimental Mtb infection [17,18] (Figure 1). It can signal via a membrane-bound receptor (cis) or, after proteolytic cleavage of the IL-6 receptor (R) from the cell membrane, via a soluble receptor (trans) (Figure 2) [72]
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