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The inflammatory cytokine tumor necrosis factor alpha (TNF-alpha) is rapidly induced in macrophages after exposure to Mycobacterium tuberculosis. Recently it was shown that lipoarabinomannan (LAM) derived from an attenuated (H37Ra) strain of M. tuberculosis (AraLAM) was capable of macrophage activation and induction of TNF-alpha production, whereas LAM derived from the virulent Erdman strain (ManLAM) was considerably reduced in this activity. A critical component in the regulation of many genes central to immune function is the transcription factor NF-kappa B. Lipopolysaccharide (LPS)-mediated induction of TNF-alpha expression in murine macrophages has been demonstrated to be regulated in part by NF-kappa B. In this study, we demonstrate that AraLAM is capable of rapid activation of NF-kappa B- and KBF1-binding activities in C3H/HeN bone marrow-derived macrophages and the J774.A and RAW264.7 murine macrophagelike cell lines, whereas ManLAM is considerably less potent at stimulating NF-kappa B. Treatment of RAW264.7 cells with AraLAM or LPS results in the stimulation of DNA binding of both forms within 7.5 min, which peaks within 30 min and 1 h, respectively. Interestingly, treatment of RAW264.7 macrophage-like cells with AraLAM, LPS, or ManLAM for greater than 2 h resulted in significant accumulation of KBF1. Inhibition of protein synthesis blocked the transient nature of NF-kappa B activation as well as the accumulation of KBF1. Using Western immunodetection of the NF kappa B1 p50 subunit, we also show that AraLAM and LPS stimulate the loss of the NF kappa B1 p105 precursor. These results demonstrate that NF-kappa B and KBF1 are rapidly induced in response to AraLAM and may play a role in avirulent M. tuberculosis activation of TNF-alpha expression in macrophages. The differential temporal regulation of kappa B element DNA-binding activities and the transient stimulation of NF kappa B followed by the sustained accumulation of KBF1 may serve as a feedback switch ensuring transient induction of TNF-alpha transcription.

infection and immunity

Lipoarabinomannans derived from different strains of Mycobacterium tuberculosis differentially stimulate the activation of NF-kappa B and KBF1 in murine macrophages