In Vivo IL-10 Production Reactivates Chronic Pulmonary Tuberculosis in C57BL/6 Mice

Abstract

The production of immunosuppressive cytokines, such as IL-10 and TGF-β, has been documented in individuals diagnosed with active tuberculosis. In addition, IL-10 production is increased within the lungs of mice that have chronic mycobacterial infection. Therefore, we hypothesized that the down-regulatory properties of IL-10 might contribute to the reactivation of chronic Mycobacterium tuberculosis infection in mice. To determine the influence of IL-10 on the course of infection, transgenic mice producing increased amounts of IL-10 under the control of the IL-2 promotor were infected with M. tuberculosis via the respiratory route. Mice that overexpressed IL-10 showed no increase in susceptibility during the early stages of infection, but during the chronic phase of the infection showed evidence of reactivation tuberculosis with a highly significant increase in bacterial numbers within the lungs. Reactivation was associated with the formation of macrophage-dominated lesions, decreased mRNA production for TNF and IL-12p40, and a decrease in Ag-specific IFN-γ secretion. These data support the hypothesis that IL-10 plays a pivotal role during the chronic/latent stage of pulmonary tuberculosis, with increased production playing a potentially central role in promoting reactivation tuberculosis.

Endocytosis of Mycobacterium tuberculosis Heat Shock Protein 60 Is Required to Induce Interleukin-10 Production in Macrophages*

“…One of the possible mechanisms by which Mtbhsp60 blocks IL-12 p40 induction could be through induction of anti-inflammatory mediators like IL-10. The IL-10 cytokine has been shown to inhibit IL-12 p40 induction in macrophages (6,30,31) primarily by targeting the c-Rel transcription factor (32). Therefore, it may be possible that Mtbhsp60 predominantly activates IL-10 production through its interaction with TLR2, which subsequently inhibits c-REL vis à vis IL-12 p40 in activated macrophages (29).We also found that interaction of Mtbhsp60 with TLR4 but not TLR2 resulted in increased production of IL-12 (29).…”

A deletion defining a common Asian lineage ofMycobacterium tuberculosisassociates with immune subversion

“…4B). A considerable body of evidence indicates that IL-10 diminishes macrophage microbicidal capacity (14)(15)(16)(17). In summary, therefore, infection with CH and CAS2 were associated with a pattern of cytokine secretion that would result in phagocyte deactivation favoring the intracellular survival of bacilli.…”

Tumor Necrosis Factor Blockade in Chronic Murine Tuberculosis Enhances Granulomatous Inflammation and Disorganizes Granulomas in the Lungs

“…The mechanism underlying the latter observation is unclear, but may be a reflection of the host's attempt to counter the TNF blockade-induced increase in lung inflammation via the immunosuppressive effect of IL-10 (5, 10). Additionally, C57BL/6 transgenic mice producing increased amounts of IL-10 under control of the IL-2 promoter were shown, in a previous study, to have disorganized granuloma structures and reactivated persistent chronic tuberculosis when aerogenically infected (39). That study suggests that increased pulmonic expression of IL-10 in MP6-XT22-treated mice could adversely affect disease outcome.…”