Deficient tumor necrosis factor-alpha production in lipoarabinomannan activated macrophages from toll-like receptor-4 deficient mice: implication for mycobacterial susceptibility.

Mice with a point mutation of toll-like receptor-4 (TLR-4) (C3H/HeJ) are hypo-responsive to LPS and more susceptible to mycobacterial infections than their control wild type (C3H/OuJ). We have previously shown that TLR-4-deficient mice produced NO in response to the mycobacterial product, ara-lipoarabinomannan (LAM), in the presence of either Interferon-beta (IFN-beta) or Interferon-gamma (IFN-gamma), with a dose response curve that produced levels of NO almost as high as those observed in C3H/OuJ mice at high concentrations of ara-LAM plus either IFN-beta or-gamma. We now report that tumor necrosis factor-alpha (TNF-alpha), an important cytokine for intracellular killing of mycobacteria, remains deficient in these C3H/HeJ mice compared to C3H/OuJ mice even at a high concentration of ara-LAM with either IFN-gamma or IFN-beta. In addition, TNF-alpha was further down regulated by taurine chloramine (Tau-Cl) in C3H/OuJ mice. The low level of TNF-alpha produced in the TLR-4-deficient (C3H/HeJ) mice was also further down regulated by Tau-Cl. These findings implicate the TLR-4 as an additional candidate locus for mycobacterial susceptibility, and provide a pathway for better understanding the molecular basis of this locus in the immunopathogenesis of mycobacterial infection.