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Background  Macrophages are the primary effector cells responsible for killing  Mycobacterium tuberculosis  ( MTB ) through various mechanisms, including apoptosis. However,  MTB  can evade host immunity to create a favorable environment for intracellular replication.  MTB -infected human macrophages produce interleukin-32 (IL-32). IL-32 is a pro-inflammatory cytokine and has several isoforms. We previously found that IL-32γ reduced the burden of  MTB  in human macrophages, in part, through the induction of caspase-3-dependent apoptosis. However, based on our previous studies, we hypothesized that caspase-3- independent  death pathways may also mediate IL-32 control of  MTB  infection. Herein, we assessed the potential roles of cathepsin-mediated apoptosis, caspase-1-mediated pyroptosis, and apoptosis-inducing factor (AIF) in mediating IL-32γ control of  MTB  infection in THP-1 cells.    Results  Differentiated human THP-1 macrophages were infected with  MTB  H37Rv alone or in the presence of specific inhibitors to caspase-1, cathepsin B/D, or cathepsin L for up to four days, after which TUNEL-positive cells were quantified; in addition,  MTB  was quantified by culture as well as by the percentage of THP-1 cells that were infected with green fluorescent protein (GFP)-labeled  MTB  as determined by microscopy. AIF expression was inhibited using siRNA technology. Inhibition of cathepsin B/D, cathepsin L, or caspase-1 activity significantly abrogated the IL-32γ-mediated reduction in the number of intracellular  MTB  and of the percentage of GFP- MTB -infected macrophages. Furthermore, inhibition of caspase-1, cathepsin B/D, or cathepsin L in the absence of exogenous IL-32γ resulted in a trend toward an increased proportion of  MTB -infected THP-1 cells. Inhibition of AIF activity in the absence of exogenous IL-32γ also increased intracellular burden of  MTB . However, since IL-32γ did not induce AIF and because the relative increases in  MTB  with inhibition of AIF were similar in the presence or absence of IL-32γ, our results indicate that AIF does not mediate the host-protective effect of IL-32γ against  MTB .    Conclusions  The anti- MTB  effects of IL-32γ are mediated through classical caspase-3-dependent apoptosis as well as caspase-3-independent apoptosis.

Caspase-3-independent apoptotic pathways contribute to interleukin-32γ-mediated control of Mycobacterium tuberculosis infection in THP-1 cells