Anti-inflammatory treatment of chronic inflammatory diseases often increases susceptibility to infectious diseases such as tuberculosis (TB). Since numerous chronic inflammatory and autoimmune diseases are mediated by interleukin (IL)-6-induced T helper (TH) 17 cells, a TH17-directed anti-inflammatory therapy may be preferable to an IL-12-dependent TH1 inhibition in order to avoid reactivation of latent infections. To assess, however, the risk of inhibition of IL-6-dependent TH17-mediated inflammation, we examined the TH17 immune response and the course of experimental TB in IL-6- and T-cell-specific gp130-deficient mice. Our study revealed that the absence of IL-6 or gp130 on T cells has only a minor effect on the development of antigen-specific TH1 and TH17 cells. Importantly, these gene-deficient mice were as capable as wild type mice to control mycobacterial infection. Together, in contrast to its key function for TH17 development in other inflammatory diseases, IL-6 plays an inferior role for the generation of TH17 immune responses during experimental TB.

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.

During experimental tuberculosis (TB), interleukin (IL)-17A appears to be involved in the formation of lung granulomas, possibly through the attraction of neutrophils to the sites of infection. However, the protective impact of cytokine appears to depend on the degree of its induction. Hence, robust production of IL-17A in mice infected with the hypervirulent isolate Mycobacterium tuberculosis (Mtb) HN878 mediates protection, while the cytokine is dispensable for protective immune responses against low-dose infection with the less virulent strain H37rv. Here, we show that after experimental infection with high doses of Mtb H37rv, IL-17A-deficient (^−/−) mice exhibited high susceptibility to the infection, which was mediated by the strong accumulation of neutrophils in the infected lung tissue. Accordingly, we observed nearly unrestricted bacterial replication within the neutrophils, indicating that they may serve as a survival niche for Mtb. By use of IL-17A/IL-17F-double-deficient mice, we demonstrated that the susceptibility in the absence of IL-17A is mediated by a compensatory expression of IL-17F, which, however, appeared not to be dependent on neutrophils. Together, our results illustrate the compensatory potential of the Th17-secreted cytokines IL-17A and IL-17F in the context of experimental TB and once again emphasize the detrimental effect of excessive neutrophil infiltration in response to Mtb.