Endotoxin-Induced Maturation of MyD88-Deficient Dendritic Cells

• Published in: The Journal of immunology (1950) Vol. 166; no. 9; pp. 5688 - 5694
• Main Authors: Kaisho, Tsuneyasu, Takeuchi, Osamu, Kawai, Taro, Hoshino, Katsuaki, Akira, Shizuo
• Format: Journal Article
• Language: English
• Published: United States Am Assoc Immnol 01.05.2001
• Subjects: Adaptor Proteins, Signal Transducing; Adjuvants, Immunologic - administration & dosage; Adjuvants, Immunologic - pharmacology; Animals; Antigens, CD - biosynthesis; Antigens, Differentiation - biosynthesis; Antigens, Differentiation - genetics; Antigens, Differentiation - physiology; B7-2 Antigen; Bone Marrow Cells - immunology; Bone Marrow Cells - metabolism; CD40 Antigens - biosynthesis; Cell Differentiation - genetics; Cell Differentiation - immunology; Cell Membrane - genetics; Cell Membrane - immunology; Cell Membrane - metabolism; Cells, Cultured; Cytokines - biosynthesis; Dendritic Cells - cytology; Dendritic Cells - immunology; Dendritic Cells - metabolism; DNA-Binding Proteins - physiology; Drosophila Proteins; Injections, Intravenous; Lipopolysaccharides - administration & dosage; Lipopolysaccharides - pharmacology; Membrane Glycoproteins - biosynthesis; Membrane Glycoproteins - deficiency; Membrane Glycoproteins - genetics; Membrane Glycoproteins - physiology; Mice; Mice, Inbred BALB C; Mice, Inbred C3H; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; MyD88 protein; Myeloid Differentiation Factor 88; Receptors, Cell Surface - deficiency; Receptors, Cell Surface - genetics; Receptors, Cell Surface - physiology; Receptors, Immunologic; Signal Transduction - genetics; Signal Transduction - immunology; Species Specificity; Spleen - cytology; Spleen - immunology; TLR4 protein; Toll-Like Receptor 4; Toll-Like Receptor 9; Toll-Like Receptors
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.166.9.5688

LPS, a major component of the cell wall of Gram-negative bacteria, can induce a variety of biological responses including cytokine production from macrophages, B cell proliferation, and endotoxin shock. All of them were completely abolished in MyD88-deficient mice, indicating the essential role of MyD88 in LPS signaling. However, MyD88-deficient cells still show activation of NF-kappaB and mitogen-activated protein kinase cascades, although the biological significance of this activation is not clear. In this study, we have examined the effects of LPS on dendritic cells (DCs) from wild-type and several mutant mice. LPS-induced cytokine production from DCs was dependent on MyD88. However, LPS could induce functional maturation of MyD88-deficient DCs, including up-regulation of costimulatory molecules and enhancement of APC activity. MyD88-deficient DCs could not mature in response to bacterial DNA, the ligand for Toll-like receptor (TLR)9, indicating that MyD88 is differentially required for TLR family signaling. MyD88-dependent and -independent pathways originate at the intracytoplasmic region of TLR4, because both cytokine induction and functional maturation were abolished in DCs from C3H/HeJ mice carrying the point mutation in the region. Finally, in vivo analysis revealed that MyD88-, but not TLR4-, deficient splenic CD11c(+) DCs could up-regulate their costimulatory molecule expression in response to LPS. Collectively, the present study provides the first evidence that the MyD88-independent pathway downstream of TLR4 can lead to functional DC maturation, which is critical for a link between innate and adaptive immunity.