Regulation of signal transduction through toll like receptors (interleukin-1 receptor related) by stimulation of live Mycobacterium tuberculosis

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We have previously revealed that live, but not dead, Mycobacterium tuberculosis exhibits cytotoxicity to human lung fibroblast cell line (J. Interferon Cytokine Res., 2001, Antimicrob. Agents Chemother., 2002). In order to investigate the signal transduction from live bacteria to host cell, we studied the expression of toll like receptors (TLRs), which are related to interleukin 1 receptor (IL-1R), and signal transduction from the receptors after stimulation with live bacilli. Lipoproteins which are present in cell wall of mycobacteria are reported as major ligand to TLR2 and induces apoptosis of macrophages. Lipopolysaccharide present in cell wall of gram-negative bacteria, transducer its signal through TLR4. In this study, LPS and transforming growth factor beta are revealed to regulate the expression of TLR2 and TLR4 on mouse hepatocyte (Immunology, 2003, J. Leukocyto Biol., 2004). Human fibroblast cell line, MRC-5, is known to constitutively expresses TLR1-10. The mechanism of activation of NF-kB is closely related to that of IL-1R. Therefore, we have investigated the activation of NF-kB on MRC-5 after stimulation of live M. tuberculosis. Live, but not dead, bacilli strongly induces NF kB and also induce expression of inflammatrical cytokines. Interestingly, the kinetics of induction of NF-kB and cytokines are similar to that of the effect of cytotoxicity of live bacilli. These data suggests that the signaling from TLRs after stimulation of live bacilli would have significance on the cytotoxicity to human cell. Further, we were also successful in applying the cytotoxicity testing for susceptibility test to pyrazinamic acid using clinical isolates of tuberculosis (Antimicrob. Agents Chemother., 2005)