MD-2 Enables Toll-Like Receptor 2 (TLR2)-Mediated Responses to Lipopolysaccharide and Enhances TLR2-Mediated Responses to Gram-Positive and Gram-Negative Bacteria and Their Cell Wall Components

• Published in: The Journal of immunology (1950) 2001-02, Vol.166 (3), p.1938-1944
• Main Authors: Dziarski, Roman, Wang, Qiuling, Miyake, Kensuke, Kirschning, Carsten J, Gupta, Dipika
• Format: Article
• Language: English
• Subjects: Adjuvants, Immunologic - metabolism; Adjuvants, Immunologic - physiology; Antigens, Surface - metabolism; Antigens, Surface - physiology; B-Lymphocytes - immunology; Cell Line; Cell Wall - immunology; Drosophila Proteins; Gram-Negative Bacteria - immunology; Gram-Positive Bacteria - immunology; Humans; Lipopolysaccharides - immunology; Lipopolysaccharides - isolation & purification; Lipopolysaccharides - metabolism; Lipopolysaccharides - toxicity; Lipoproteins - immunology; Lymphocyte Activation; Lymphocyte Antigen 96; MD-2 protein; Membrane Glycoproteins - biosynthesis; Membrane Glycoproteins - genetics; Membrane Glycoproteins - metabolism; Membrane Glycoproteins - physiology; Peptidoglycan - immunology; Polysaccharides - immunology; Receptors, Cell Surface - biosynthesis; Receptors, Cell Surface - genetics; Receptors, Cell Surface - metabolism; Receptors, Cell Surface - physiology; Solubility; Teichoic Acids - immunology; TLR2 protein; Toll-Like Receptor 2; Toll-Like Receptor 4; Toll-Like Receptors; Transfection
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.166.3.1938

MD-2 is associated with Toll-like receptor 4 (TLR4) on the cell surface and enables TLR4 to respond to LPS. We tested whether MD-2 enhances or enables the responses of both TLR2 and TLR4 to Gram-negative and Gram-positive bacteria and their components. TLR2 without MD-2 did not efficiently respond to highly purified LPS and LPS partial structures. MD-2 enabled TLR2 to respond to nonactivating protein-free LPS, LPS mutants, or lipid A and enhanced TLR2-mediated responses to both Gram-negative and Gram-positive bacteria and their LPS, peptidoglycan, and lipoteichoic acid components. MD-2 enabled TLR4 to respond to a wide variety of LPS partial structures, Gram-negative bacteria, and Gram-positive lipoteichoic acid, but not to Gram-positive bacteria, peptidoglycan, and lipopeptide. MD-2 physically associated with TLR2, but this association was weaker than with TLR4. MD-2 enhanced expression of both TLR2 and TLR4, and TLR2 and TLR4 enhanced expression of MD-2. Thus, MD-2 enables both TLR4 and TLR2 to respond with high sensitivity to a broad range of LPS structures and to lipoteichoic acid, and, moreover, MD-2 enhances the responses of TLR2 to Gram-positive bacteria and peptidoglycan, to which the TLR4-MD-2 complex is unresponsive.