DOI: 10.4049/jimmunol.167.10.5887. Lipopolysaccharide Stimulates the MyD88-Independent Pathway and Results in Activation of IFN-Regulatory Factor 3 and the Expression of a Subset of Lipopolysaccharide-Inducible Genes

Lipopolysaccharide Stimulates the MyD88-Independent Pathway and Results in Activation of IFN-Regulatory Factor 3 and the Expression of a Subset of Lipopolysaccharide-Inducible Genes

10.4049/jimmunol.167.10.5887

Crossref journal-article

Oxford University Press (OUP)

The Journal of Immunology (286)

Abstract

AbstractBacterial lipopolysaccharide (LPS) triggers innate immune responses through Toll-like receptor (TLR) 4, a member of the TLR family that participates in pathogen recognition. TLRs recruit a cytoplasmic protein, MyD88, upon pathogen recognition, mediating its function for immune responses. Two major pathways for LPS have been suggested in recent studies, which are referred to as MyD88-dependent and -independent pathways. We report in this study the characterization of the MyD88-independent pathway via TLR4. MyD88-deficient cells failed to produce inflammatory cytokines in response to LPS, whereas they responded to LPS by activating IFN-regulatory factor 3 as well as inducing the genes containing IFN-stimulated regulatory elements such as IP-10. In contrast, a lipopeptide that activates TLR2 had no ability to activate IFN-regulatory factor 3. The MyD88-independent pathway was also activated in cells lacking both MyD88 and TNFR-associated factor 6. Thus, TLR4 signaling is composed of at least two distinct pathways, a MyD88-dependent pathway that is critical to the induction of inflammatory cytokines and a MyD88/TNFR-associated factor 6-independent pathway that regulates induction of IP-10.

Bibliography

Kawai, T., Takeuchi, O., Fujita, T., Inoue, J., MuÌhlradt, P. F., Sato, S., Hoshino, K., & Akira, S. (2001). Lipopolysaccharide Stimulates the MyD88-Independent Pathway and Results in Activation of IFN-Regulatory Factor 3 and the Expression of a Subset of Lipopolysaccharide-Inducible Genes. The Journal of Immunology, 167(10), 5887â5894.

Authors 8

Taro Kawai (first)
Osamu Takeuchi (additional)
Takashi Fujita (additional)
Jun-ichiro Inoue (additional)
Peter F. Mühlradt (additional)
Shintaro Sato (additional)
Katsuaki Hoshino (additional)
Shizuo Akira (additional)

References 52 Referenced 854

Dates

Type	When
Created	11 years, 4 months ago (April 20, 2014, 10:55 p.m.)
Deposited	7 months, 4 weeks ago (Jan. 2, 2025, 11:52 a.m.)
Indexed	6 days, 5 hours ago (Aug. 24, 2025, 7:07 p.m.)
Issued	23 years, 9 months ago (Nov. 15, 2001)
Published	23 years, 9 months ago (Nov. 15, 2001)
Published Print	23 years, 9 months ago (Nov. 15, 2001)

Funders 0

None

BibTeX

@article{Kawai_2001, title={Lipopolysaccharide Stimulates the MyD88-Independent Pathway and Results in Activation of IFN-Regulatory Factor 3 and the Expression of a Subset of Lipopolysaccharide-Inducible Genes}, volume={167}, ISSN={1550-6606}, url={http://dx.doi.org/10.4049/jimmunol.167.10.5887}, DOI={10.4049/jimmunol.167.10.5887}, number={10}, journal={The Journal of Immunology}, publisher={Oxford University Press (OUP)}, author={Kawai, Taro and Takeuchi, Osamu and Fujita, Takashi and Inoue, Jun-ichiro and Mühlradt, Peter F. and Sato, Shintaro and Hoshino, Katsuaki and Akira, Shizuo}, year={2001}, month=nov, pages={5887–5894} }

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  "abstract": "<jats:title>Abstract</jats:title><jats:p>Bacterial lipopolysaccharide (LPS) triggers innate immune responses through Toll-like receptor (TLR) 4, a member of the TLR family that participates in pathogen recognition. TLRs recruit a cytoplasmic protein, MyD88, upon pathogen recognition, mediating its function for immune responses. Two major pathways for LPS have been suggested in recent studies, which are referred to as MyD88-dependent and -independent pathways. We report in this study the characterization of the MyD88-independent pathway via TLR4. MyD88-deficient cells failed to produce inflammatory cytokines in response to LPS, whereas they responded to LPS by activating IFN-regulatory factor 3 as well as inducing the genes containing IFN-stimulated regulatory elements such as IP-10. In contrast, a lipopeptide that activates TLR2 had no ability to activate IFN-regulatory factor 3. The MyD88-independent pathway was also activated in cells lacking both MyD88 and TNFR-associated factor 6. Thus, TLR4 signaling is composed of at least two distinct pathways, a MyD88-dependent pathway that is critical to the induction of inflammatory cytokines and a MyD88/TNFR-associated factor 6-independent pathway that regulates induction of IP-10.</jats:p>",
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      "key": "2022123116410106700_R1",
      "doi-asserted-by": "crossref",
      "unstructured": "Medzhitov, R., C. A. Janeway, Jr. 1997. Innate immunity: the virtues of a nonclonal system of recognition. Cell\u200891: 295",
      "DOI": "10.1016/S0092-8674(00)80412-2"
    },
    {
      "key": "2022123116410106700_R2",
      "doi-asserted-by": "crossref",
      "unstructured": "Janeway, C. A., Jr, R. Medzhitov. 1999. Lipoproteins take their Toll on the host. Curr. Biol.\u20089: R879",
      "DOI": "10.1016/S0960-9822(00)80073-1"
    },
    {
      "key": "2022123116410106700_R3",
      "doi-asserted-by": "crossref",
      "unstructured": "Hoffmann, J. A., F. C. Kafatos, C. A. Janeway, Jr, R. A. Ezekowitz. 1999. Phylogenetic perspectives in innate immunity. Science\u2008284: 1313",
      "DOI": "10.1126/science.284.5418.1313"
    },
    {
      "key": "2022123116410106700_R4",
      "doi-asserted-by": "crossref",
      "unstructured": "Medzhitov, R., P. Preston-Hurburt, C. A. Janeway, Jr. 1997. A human homologue of the Drosophila Toll protein signals activation of adaptive immunity. Nature\u2008388: 394",
      "DOI": "10.1038/41131"
    },
    {
      "key": "2022123116410106700_R5",
      "doi-asserted-by": "crossref",
      "unstructured": "Rock, F. L., G. Hardiman, J. C. Timans, R. A. Kastelein, J. F. Bazan. 1998. A family of human receptors structurally related to Drosophila Toll. Proc. Natl. Acad. Sci. USA\u200895: 588",
      "DOI": "10.1073/pnas.95.2.588"
    },
    {
      "key": "2022123116410106700_R6",
      "doi-asserted-by": "crossref",
      "unstructured": "Takeuchi, O., T. Kawai, H. Sanjo, N. G. Copeland, D. J. Gilbert, N. A. Jenkins, K. Takeda, S. Akira. 1999. TLR6: a novel member of an expanding Toll-like receptor family. Gene\u2008231: 59",
      "DOI": "10.1016/S0378-1119(99)00098-0"
    },
    {
      "key": "2022123116410106700_R7",
      "unstructured": "Chuang, T. H., R. J. Ulevitch. 2000. Cloning and characterization of a subfamily of human Toll-like receptors: hTLR7, hTLR8, and hTLR9. Eur. Cytokine Network\u200811: 372"
    },
    {
      "key": "2022123116410106700_R8",
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      "DOI": "10.1038/35047123"
    },
    {
      "key": "2022123116410106700_R9",
      "doi-asserted-by": "crossref",
      "unstructured": "Ulevitch, R. J., P. S. Tobias. 1995. Receptor-dependent mechanisms of cell stimulation by bacterial endotoxin. Annu. Rev. Immunol.\u200813: 437",
      "DOI": "10.1146/annurev.iy.13.040195.002253"
    },
    {
      "key": "2022123116410106700_R10",
      "doi-asserted-by": "crossref",
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      "DOI": "10.1126/science.282.5396.2085"
    },
    {
      "key": "2022123116410106700_R11",
      "doi-asserted-by": "crossref",
      "unstructured": "Hoshino, K., O. Takeuchi, T. Kawai, H. Sanjo, T. Ogawa, Y. Takeda, K. Takeda, S. Akira. 1999. TLR4-deficient mice are hyporesponsive to LPS: evidence for TLR4 as the Lps gene product. J. Immunol.\u2008162: 3749",
      "DOI": "10.4049/jimmunol.162.7.3749"
    },
    {
      "key": "2022123116410106700_R12",
      "doi-asserted-by": "crossref",
      "unstructured": "Takeuchi, O., K. Hoshino, T. Kawai, H. Sanjo, H. Takada, T. Ogawa, K. Takeda, S. Akira. 1999. Differential roles of TLR2 and TLR4 in recognition of Gram-negative and Gram-positive bacterial cell wall components. Immunity\u200811: 443",
      "DOI": "10.1016/S1074-7613(00)80119-3"
    },
    {
      "key": "2022123116410106700_R13",
      "doi-asserted-by": "crossref",
      "unstructured": "Takeuchi, O., A. Kaufmann, K. Grote, T. Kawai, K. Hoshino, M. Morr, P. F. Muhlradt, S. Akira. 2000. Preferentially the R-stereoisomer of the mycoplasmal lipopeptide macrophage-activating lipopeptide-2 activates immune cells through a Toll-like receptor 2- and MyD88-dependent signaling pathway. J. Immunol.\u2008164: 554",
      "DOI": "10.4049/jimmunol.164.2.554"
    },
    {
      "key": "2022123116410106700_R14",
      "doi-asserted-by": "crossref",
      "unstructured": "Bowie, A., L. A. O\u2019Neill. 2000. The interleukin-1 receptor/Toll-like receptor superfamily: signal generators for proinflammatory interleukins and microbial products. J. Leukocyte Biol.\u200867: 508",
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    },
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      "key": "2022123116410106700_R15",
      "doi-asserted-by": "crossref",
      "unstructured": "Muzio, M., J. Ni, P. Feng, V. M. Dixit. 1997. IRAK (Pelle) family member IRAK-2 and MyD88 as proximal mediators of IL-1 signaling. Science\u2008278: 1612",
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    },
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      "doi-asserted-by": "crossref",
      "unstructured": "Wesche, H., W. J. Henzel, W. Shillinglaw, S. Li, Z. Cao. 1997. MyD88: an adaptor protein that recruits IRAK to the IL-1 receptor complex. Immunity\u20087: 837",
      "DOI": "10.1016/S1074-7613(00)80402-1"
    },
    {
      "key": "2022123116410106700_R17",
      "doi-asserted-by": "crossref",
      "unstructured": "Medzhitov, R., P. Preston-Hurlburt, E. Kopp, A. Stadlen, C. Chen, S. Ghosh, C. A. Janeway, Jr. 1998. MyD88 is an adaptor protein in the hToll/IL-1 receptor family signaling pathways. Mol. Cell.\u20082: 253",
      "DOI": "10.1016/S1097-2765(00)80136-7"
    },
    {
      "key": "2022123116410106700_R18",
      "doi-asserted-by": "crossref",
      "unstructured": "Cao, Z., W. J. Henzel, X. Gao. 1996. IRAK: a kinase associated with the interleukin-1 receptor. Science\u2008271: 1128",
      "DOI": "10.1126/science.271.5252.1128"
    },
    {
      "key": "2022123116410106700_R19",
      "doi-asserted-by": "crossref",
      "unstructured": "Cao, Z., J. Xiong, M. Takeuchi, T. Kurama, D. V. Goeddel. 1996. TRAF6 is a signal transducer for interleukin-1. Nature\u2008383: 443",
      "DOI": "10.1038/383443a0"
    },
    {
      "key": "2022123116410106700_R20",
      "doi-asserted-by": "crossref",
      "unstructured": "Adachi, O., T. Kawai, K. Takeda, M. Matsumoto, H. Tsutsui, M. Sakagami, K. Nakanishi, S. Akira. 1998. Targeted disruption of the MyD88 gene results in loss of IL-1- and IL-18-mediated function. Immunity\u20089: 143",
      "DOI": "10.1016/S1074-7613(00)80596-8"
    },
    {
      "key": "2022123116410106700_R21",
      "doi-asserted-by": "crossref",
      "unstructured": "Kawai, T., O. Adachi, T. Ogawa, K. Takeda, S. Akira. 1999. Unresponsiveness of MyD88-deficient mice to endotoxin. Immunity\u200811: 115",
      "DOI": "10.1016/S1074-7613(00)80086-2"
    },
    {
      "key": "2022123116410106700_R22",
      "doi-asserted-by": "crossref",
      "unstructured": "Yoneyama, M., W. Suhara, Y. Fukuhara, M. Fukuda, E. Nishida, T. Fujita. 1998. Direct triggering of the type I interferon system by virus infection: activation of a transcription factor complex containing IRF-3 and CBP/p300. EMBO J.\u200817: 1087",
      "DOI": "10.1093/emboj/17.4.1087"
    },
    {
      "key": "2022123116410106700_R23",
      "doi-asserted-by": "crossref",
      "unstructured": "Shimada, T., M. Matsumoto, Y. Tatsumi, A. Kanamaru, S. Akira. 1998. A novel lipopolysaccharide inducible C-C chemokine receptor related gene in murine macrophages. FEBS Lett.\u2008425: 490",
      "DOI": "10.1016/S0014-5793(98)00299-3"
    },
    {
      "key": "2022123116410106700_R24",
      "doi-asserted-by": "crossref",
      "unstructured": "Reich, N., B. Evans, D. Levy, D. Fahey, E. Knight, Jr, J. E. Darnell, Jr. 1987. IFN-induced transcription of a gene encoding a 15-kDa protein depends on an upstream enhancer element. Proc. Natl. Acad. Sci. USA\u200884: 6394",
      "DOI": "10.1073/pnas.84.18.6394"
    },
    {
      "key": "2022123116410106700_R25",
      "doi-asserted-by": "crossref",
      "unstructured": "Ohmori, Y., T. A. Hamilton. 1993. Cooperative interaction between interferon (IFN) stimulus response element and \u03baB sequence motifs controls IFN-\u03b3- and lipopolysaccharide-stimulated transcription from the murine IP-10 promoter. J. Biol. Chem.\u2008268: 6677",
      "DOI": "10.1016/S0021-9258(18)53303-2"
    },
    {
      "key": "2022123116410106700_R26",
      "doi-asserted-by": "crossref",
      "unstructured": "Lee, C.G., N. A. Jenkins, D. J. Gilbert, N. G. Copeland, W. E. O\u2019Brien. 1995. Cloning and analysis of gene regulation of a novel LPS-inducible cDNA. Immunogenetics\u200841: 263",
      "DOI": "10.1007/BF00172150"
    },
    {
      "key": "2022123116410106700_R27",
      "doi-asserted-by": "crossref",
      "unstructured": "Smith, J. B., H. R. Herschman. 1996. The glucocorticoid-attenuated response genes GARG-16, GARG-39, and GARG-49/IRG2 encode inducible proteins containing multiple tetratricopeptide repeat domains. Arch. Biochem. Biophys.\u2008330: 290",
      "DOI": "10.1006/abbi.1996.0256"
    },
    {
      "key": "2022123116410106700_R28",
      "doi-asserted-by": "crossref",
      "unstructured": "Wathelet, M. G., I. M. Clauss, C. B. Nols, J. Content, G. A. Huez. 1987. New inducers revealed by the promoter sequence analysis of two interferon-activated human genes. Eur. J. Biochem.\u2008169: 313",
      "DOI": "10.1111/j.1432-1033.1987.tb13614.x"
    },
    {
      "key": "2022123116410106700_R29",
      "doi-asserted-by": "crossref",
      "unstructured": "Wathelet, M. G., I. M. Clauss, J. Content, G. A. Huez. 1988. Regulation of two interferon-inducible human genes by interferon, poly(rI), poly(rC), and viruses. Eur. J. Biochem.\u2008174: 323",
      "DOI": "10.1111/j.1432-1033.1988.tb14101.x"
    },
    {
      "key": "2022123116410106700_R30",
      "doi-asserted-by": "crossref",
      "unstructured": "Kopidlowski, K. M., C. A. Salkowski, M. Joshua Cody, N. van Rooijen, J. Major, T. A. Hamilton, S. N. Vogel. 1999. Regulation of macrophage chemokine expression by lipopolysaccharide in vitro and in vivo. J. Immunol.\u2008163: 1537",
      "DOI": "10.4049/jimmunol.163.3.1537"
    },
    {
      "key": "2022123116410106700_R31",
      "doi-asserted-by": "crossref",
      "unstructured": "Ding, A. H., F. Porteu, E. Sanchez, C. F. Nathan. 1990. Shared actions of endotoxin and Taxol on TNF receptors and TNF release. Science\u2008248: 370",
      "DOI": "10.1126/science.1970196"
    },
    {
      "key": "2022123116410106700_R32",
      "doi-asserted-by": "crossref",
      "unstructured": "Manthey, C. L., M. E. Brandes, P. Y. Perera, S. N. Vogel. 1992. Taxol increases steady state levels of lipopolysaccharide-inducible genes and protein-tyrosine phosphorylation in murine macrophages. J. Immunol.\u2008149: 2459",
      "DOI": "10.4049/jimmunol.149.7.2459"
    },
    {
      "key": "2022123116410106700_R33",
      "doi-asserted-by": "crossref",
      "unstructured": "Kawasaki, K., S. Akashi, R. Shimazu, T. Yoshida, K. Miyake, M. Nishijima. 2000. Mouse toll-like receptor 4: MD-2 complex mediates lipopolysaccharide-mimetic signal transduction by Taxol. J. Biol. Chem.\u2008275: 2251",
      "DOI": "10.1074/jbc.275.4.2251"
    },
    {
      "key": "2022123116410106700_R34",
      "doi-asserted-by": "crossref",
      "unstructured": "Cheng, G., A. S. Nazar, H. S. Shin, P. Vanguri, M. L. Shin. 1998. IP-10 gene transcription by virus in astrocytes requires cooperation of ISRE with adjacent \u03baB site but not IRF-1 or viral transcription. J. Interferon Cytokine Res.\u200818: 987",
      "DOI": "10.1089/jir.1998.18.987"
    },
    {
      "key": "2022123116410106700_R35",
      "doi-asserted-by": "crossref",
      "unstructured": "Lin, R., C. Heylbroeck, P. Genin, P. M. Pitha, J. Hiscott. 1999. Essential role of interferon regulatory factor-3 in direct activation of RANTES chemokine transcription. Mol. Cell. Biol.\u200819: 959",
      "DOI": "10.1128/MCB.19.2.959"
    },
    {
      "key": "2022123116410106700_R36",
      "doi-asserted-by": "crossref",
      "unstructured": "Kim, T., T. Y. Kim, Y. H. Song, I. M. Min, J. Yim, T. K. Kim. 1999. Activation of interferon regulatory factor-3 in response to DNA-damaging agents. J. Biol. Chem.\u2008274: 30686",
      "DOI": "10.1074/jbc.274.43.30686"
    },
    {
      "key": "2022123116410106700_R37",
      "doi-asserted-by": "crossref",
      "unstructured": "Lin, R., C. Heylbroeck, P. M. Pitha, J. Hiscott. 1998. Virus-dependent phosphorylation of the IRF-3 transcription factor regulates nuclear translocation, transactivation potential, and proteasome-mediated degradation. Mol. Cell. Biol.\u200818: 2986",
      "DOI": "10.1128/MCB.18.5.2986"
    },
    {
      "key": "2022123116410106700_R38",
      "doi-asserted-by": "crossref",
      "unstructured": "Au, W. C., P. A. Moore, W. Lowther, Y. T. Juang, P. M. Pitha. 1995. Identification of a member of the interferon regulatory factor family that binds to the interferon-stimulated response element and activates expression of interferon-induced genes. Proc. Natl. Acad. Sci. USA\u200892: 11657",
      "DOI": "10.1073/pnas.92.25.11657"
    },
    {
      "key": "2022123116410106700_R39",
      "doi-asserted-by": "crossref",
      "unstructured": "Navarro, L., K. Mowen, S. Rodems, B. Weaver, N. Reich, D. Spector, M. David. 1998. Cytomegalovirus activates interferon immediate early response gene expression and an interferon regulatory factor-3 containing interferon-stimulated response element-binding complex. Mol. Cell. Biol.\u200818: 3796",
      "DOI": "10.1128/MCB.18.7.3796"
    },
    {
      "key": "2022123116410106700_R40",
      "doi-asserted-by": "crossref",
      "unstructured": "Navarro, L., M. David. 1999. p38-dependent activation of interferon regulatory factor-3 by lipopolysaccharide. J. Biol. Chem.\u2008274: 35535",
      "DOI": "10.1074/jbc.274.50.35535"
    },
    {
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      "DOI": "10.1038/18465"
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