The outcome of the interaction between Mycobacterium tuberculosis (Mtb) and a macrophage depends on the interplay between host defense and bacterial immune subversion mechanisms. MicroRNAs critically regulate several host defense mechanisms, but their role in the Mtb-macrophage interplay remains unclear. MicroRNA profiling of Mtb-infected macrophages revealed the downregulation of miR-let-7f in a manner dependent on the Mtb secreted effector ESAT-6. We establish that let-7f targets A20, a feedback inhibitor of the NF-κB pathway. Expression of let-7f decreases and A20 increases with progression of Mtb infection in mice. Mtb survival is attenuated in A20-deficient macrophages, and the production of TNF, IL-1β, and nitrite, which are mediators of immunity to Mtb, is correspondingly increased. Further, let-7f overexpression diminishes Mtb survival and augments the production of cytokines including TNF and IL-1β. These results uncover a role for let-7f and its target A20 in regulating immune responses to Mtb and controlling bacterial burden.

SummaryMycobacterium tuberculosis (M.tb.) replicates in host macrophages to cause tuberculosis. We have investigated the role of miRNAs in M.tb.-infected murine RAW264.7 cells and bone marrow-derived macrophages (BMDMs), focusing on miR-155, the most highly upregulated miRNA. We observed that miR-155 upregulation is directly linked to the attenuation of expression of BTB and CNC homology 1 (Bach1) and SH2-containing inositol 5Ј-phosphatase (SHIP1). Bach1 is a transcriptional repressor of haem oxygenase-1 (HO-1), whereas SHIP1 inhibits the activation of the serine/ threonine kinase AKT. We hypothesize that M.tb.

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The present study was done to evaluate the pituitary-testicular activities of rats subjected to chronic nicotine treatment. The testicular key androgenic enzymes activities, plasma and intratesticular testosterone (ITT) concentrations, and plasma concentration of gonadotropin were significantly reduced by nicotine treatment along with the decreased sperm counts and the disruption of spermatogenesis indicated by significant reduction in the number of different generations of germ cells at stage VII of the spermatogenesis cycle with increased sperm head abnormalities. The Western blot and the reverse transcriptase-PCR analysis revealed that the nicotine induced a marked decrease in the expression of testicular steroidogenic acute regulatory (StAR) protein, which helps in the transfer of cholesterol in mitochondria for the testosterone biosynthesis. The increased testicular lipid peroxidation, plasma concentration of corticosterone, with enhanced hydrogen peroxide and hydroxyl radical generations, as well as decreased glutathione level, reduced antioxidant enzymes activities, and mitochondrial membrane potential (Deltapsi(m)) of testis, were noted after nicotine treatment in rats. Human chorionic gonadotropin or taurine supplementation with nicotine prevented the degeneration of germ cells to some extent, restored spermatogenesis moderately with decreased sperm head abnormalities, and enhanced sperm counts, accompanied with increase in plasma and ITT concentrations, testicular StAR gene expression, and key androgenic enzymes activities. Moreover, taurine supplementation to nicotine-treated animals resulted in the diminution of testicular lipid peroxidation, hydrogen peroxide and hydroxyl radical generations, with the elevation in glutathione level as well as different antioxidant enzymes activities and Deltapsi(m) in testis. The results indicated that nicotine caused testicular toxicity by germ cell degeneration, inhibition of StAR gene expression along with androgen production in adult male rats probably by affecting pituitary gonadotropin, and/or modulating the extent of testicular antioxidant status.