Gene expressions of lipopolysaccharide receptors, toll-like receptors 2 and 4, are differently regulated in mouse T lymphocytes.
Toll-like receptors (TLRs) are a family of mammalian proteins homologous to Drosophila Toll. Human TLR2 was shown to mediate the responsiveness to lipopolysaccharide (LPS). On the other hand, gene mutations of mouse TLR4 (mTLR4) in LPS-hyporesponsive strains have suggested that mTLR4 is essential for LPS-signaling in mice, but the role of mTLR2 has not been explored. This report describes molecular cloning of the mTLR2 cDNA. Overexpression of mTLR2 and mouse CD14 conferred LPS-inducibility of c-Jun N-terminal kinase phosphorylation and nuclear factor-kappaB activation to COS7 cells, suggesting that mTLR2 is a signaling receptor for LPS. Both mTLR2 and mTLR4 genes were expressed in T cells. Treatment with anti-CD3epsilon, PMA plus ionomycin, or interleukin-2 (IL-2)/IL-15 increased mTLR2 but not mTLR4 messenger RNA (mRNA) in some T cell lines. Specific inhibitors of mitogen-activated extracellular signal-regulated kinase and fusion protein 38 (p38) kinase inhibited mTLR2 mRNA up-regulation by PMA plus ionomycin. This suggests that extracellular signal-regulated kinase and p38 kinase pathways were involved. Additionally, LPS treatment of EL-4 cell line decreased IL-4 gene expression. Our results indicate that both mTLR2 and mTLR4 are involved in LPS signaling, but their expressions are regulated differently in T cells, and that LPS may directly affect T-cell functions by binding to TLRs. (Blood. 2000;95:1378-1385)
Matsuguchi
T
T
Laboratory of Host Defense and Germfree Life, Research Institute for Disease Mechanism and Control, Nagoya University School of Medicine, Nagoya, Japan. tmatsugu@med.nagoya-u.ac.jp
Takagi
K
K
Musikacharoen
T
T
Yoshikai
Y
Y
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D019556:COS Cells; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002460:Cell Line; D003001:Cloning, Molecular; D029721:Drosophila Proteins; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D018950:Lipopolysaccharide Receptors / Q000235:genetics* / Q000502:physiology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000502:physiology; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008969:Molecular Sequence Data; D009928:Organ Specificity; D011956:Receptors, Cell Surface / Q000235:genetics* / Q000502:physiology; D011994:Recombinant Proteins / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013154:Spleen / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D014158:Transcription, Genetic / Q000276:immunology* / Q000502:physiology; D014162:Transfection; D014407:Tumor Cells, Cultured; D048051:p38 Mitogen-Activated Protein Kinases
D029721:Drosophila Proteins; D004791:Enzyme Inhibitors; D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; D011994:Recombinant Proteins; C495342:TLR2 protein, human; C495345:TLR4 protein, human; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases