title: Deficient tumor necrosis factor-alpha production in lipoarabinomannan activated macrophages from toll-like receptor-4 deficient mice: implication for mycobacterial susceptibility.
abstract: 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.
authors.affiliation: Department of Dermatology, Bellevue Hospital, New York University Medical Center, Staten Island University Hospital, Department of Immunology, New York, USA.
authors.forename: William
authors.initials: W
authors.lastname: Levis
authors.forename: Georgia B
authors.initials: GB
authors.lastname: Schuller-Levis
authors.forename: Eunkyue
authors.initials: E
authors.lastname: Park
mesh_terms: D000818:Animals; D004198:Disease Susceptibility; D015536:Down-Regulation; D016899:Interferon-beta / Q000494:pharmacology; D007371:Interferon-gamma / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008562:Membrane Glycoproteins / Q000172:deficiency*; D051379:Mice; D008809:Mice, Inbred C3H; D009164:Mycobacterium Infections / Q000235:genetics*; D017354:Point Mutation; D011956:Receptors, Cell Surface / Q000172:deficiency*; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000172:deficiency
chemical_list: D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha; C050016:lipoarabinomannan; D016899:Interferon-beta; D007371:Interferon-gamma