Differential roles of Toll-like receptors in the elicitation of proinflammatory responses by macrophages

• Published in: Annals of the rheumatic diseases Vol. 60; no. suppl 3; pp. iii6 - iii12
• Main Authors: Jones, B W, Heldwein, K A, Means, T K, Saukkonen, J J, Fenton, M J
• Format: Journal Article
• Language: English
• Published: London BMJ Publishing Group Ltd and European League Against Rheumatism 01.11.2001; BMJ; BMJ Publishing Group LTD
• Subjects: Adapter proteins; Animals; Antigens, Protozoan; Bacteria; Basic-Leucine Zipper Transcription Factors; Biological and medical sciences; Cell Line; Chemokine CCL4; Chemokine CCL5 - metabolism; Cytokines; Deoxyribonucleic acid; DNA; DNA-Binding Proteins - pharmacology; Drosophila Proteins; Humans; Interferon-gamma - pharmacology; lipopolysaccharide; Lipopolysaccharides - pharmacology; Macrophage Activation - physiology; Macrophage Inflammatory Proteins - metabolism; macrophages; Macrophages - drug effects; Macrophages - metabolism; Medical sciences; Membrane Glycoproteins - genetics; Membrane Glycoproteins - physiology; Mice; Mice, Knockout; Mycobacterium tuberculosis; Nitric Oxide - metabolism; Phosphatidylinositol 3-Kinases - metabolism; Protozoan Proteins - pharmacology; Receptors, Cell Surface - genetics; Receptors, Cell Surface - physiology; Rodents; Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis; Signal transduction; Soybean Proteins; Toll-Like Receptor 2; Toll-Like Receptor 4; Toll-Like Receptors; Tuberculosis; Tumor Necrosis Factor-alpha - metabolism; Human; Cell culture; Immune response; Pathogenesis; Cytokine; Rodentia; Autoimmune disease; Activation; Cellular immunity; Inflammation; Experimental study; Chemokine; Infection; Virus; Signal transduction; Vertebrata; Mammalia; Mouse; Animal; Bacteria; Tumor necrosis factor α; Macrophage
• ISSN: 0003-4967; 1468-2060
• DOI: 10.1136/ard.60.90003.iii6

BACKGROUND Mammalian Toll-like receptor (TLR) proteins are pattern recognition receptors for a diverse array of bacterial and viral products. Gram negative bacterial lipopolysaccharide (LPS) activates cells through TLR4, whereas the mycobacterial cell wall glycolipids, lipoarabinomannan (LAM) and mannosylated phosphatidylinositol (PIM), activate cells through TLR2. Furthermore, short term culture filtrates ofM tuberculosis bacilli contain a TLR2 agonist activity, termed soluble tuberculosis factor (STF), that appears to be PIM. It was recently shown that stimulation of RAW264.7 murine macrophages by LPS, LAM, STF, and PIM rapidly activated NF-κB, AP1, and MAP kinases. RESULTS This study shows that signalling by TLR2 and TLR4 also activates the protein kinase Akt, a downstream target of phosphatidylinositol-3′-kinase (PI-3-K). This finding suggests that activation of PI-3-K represents an additional signalling pathway induced by engagement of TLR2 and TLR4. Subsequently, the functional responses induced by the different TLR agonists were compared. LPS, the mycobacterial glycolipids, and the OspC lipoprotein (a TLR2 agonist) all induced macrophages to secrete tumour necrosis factor α (TNFα), whereas only LPS could induce nitric oxide (NO) secretion. Human alveolar macrophages also exhibited a distinct pattern of cellular response after stimulation with TLR2 and TLR4 agonists. Specifically, LPS induced TNFα, MIP-1β, and RANTES production in these cells, whereas the TLR2 agonists induced only MIP-1β production. CONCLUSION Together, these data show that different TLR proteins mediate the activation of distinct cellular responses, despite their shared ability to activate NF-κB, AP1, MAP kinases, and PI-3-K.