The world's first wiki where authorship really matters (Nature Genetics, 2008). Due credit and reputation for authors. Imagine a global collaborative knowledge base for original thoughts. Search thousands of articles and collaborate with scientists around the globe.

wikigene or wiki gene protein drug chemical gene disease author authorship tracking collaborative publishing evolutionary knowledge reputation system wiki2.0 global collaboration genes proteins drugs chemicals diseases compound
Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)



Gene Review

Tlr4  -  toll-like receptor 4

Mus musculus

Synonyms: Lps, Ly87, Ran/M1, Rasl2-8, Toll-like receptor 4, ...
Welcome! If you are familiar with the subject of this article, you can contribute to this open access knowledge base by deleting incorrect information, restructuring or completely rewriting any text. Read more.

Disease relevance of Tlr4

  • Destructive mutations of Tlr4 predispose to the development of Gram-negative sepsis, leaving most aspects of immune function intact [1].
  • Defects in the gene encoding Toll-like receptor 4 (Tlr4) result in impaired responses to lipopolysaccharide (LPS), rendering mice sensitive to infections by Gram-negative bacteria [2].
  • Overexpression of Tlr4 by itself appears to have a survival advantage in Tg mice early during infection: animals possessing more than two copies of the gene survived longer and in a greater percentage to Salmonella infection [3].
  • We therefore hypothesized that protective immunity to O. volvulus would not develop in C3H/HeJ mice which have a mutation in the Tlr4 gene (TLR4 mutant), either because of a decreased Th2 response to the larvae or because of the absence of a response to Wolbachia [4].
  • MHCII, Tlr4 and Nramp1 genes control host pulmonary resistance against the opportunistic bacterium Pasteurella pneumotropica [5].

Psychiatry related information on Tlr4

  • For the time-response study, LPS (5 mg/kg i.p.) produced a rapid decrease in Oatp4 mRNA levels in TLR4-normal C3H/OuJ mice [6].

High impact information on Tlr4


Chemical compound and disease context of Tlr4


Biological context of Tlr4

  • Thus, Tlr4 is an autosomal gene whose expression is regulated similarly to that of genes on the X chromosome [2].
  • C3H/HeJ mice have a point mutation within the coding region of the Tlr4 gene, resulting in a nonconservative substitution of a highly conserved proline by histidine at codon 712, whereas C57BL/ 10ScCr mice exhibit a deletion of Tlr4 [14].
  • However, this early improvement in disease resistance is not conducted later during infection, because mice overexpressing Tlr4 developed an excessive inflammatory response detrimental to the host [3].
  • They augment the effect of LPS by inducing Tlr4 gene expression, through CRF2, via activation of the transcription factors PU.1 and AP-1 [15].
  • LPS with NECA strongly up-regulates VEGF expression by macrophages from C(3)H/HeN mice (with intact Tlr4 receptors), but not by macrophages from C(3)H/HeJ mice (with mutated, functionally inactive Tlr4 receptors), implicating signaling through the Tlr4 pathway in this synergistic up-regulation [16].

Anatomical context of Tlr4

  • Overall, the results indicate that this Hsfp can activate DC independently of LPS but still requires Tlr4 for an optimal CD8 T cell response [17].
  • Despite their impaired Tlr4 pathway, Paneth cells in ex vivo C3H/HeJ mouse crypts released equivalent amounts of bactericidal peptide activity in response to purified bacterial antigens, including lipid A [18].
  • In the current study, we evaluated the role of mCD14 and TLR4 in LPS induction of MnSOD using peritoneal macrophages from CD14 knockout (CD14-KO) mice and mice with the Tlr4 gene point mutation (C3H/HeJ) or deletion (C57BL/10ScCr) [19].
  • Mice with functional Tlr4 had reduced lung permeability, leukocyte inflammation, and primary tumor formation (BALB(Lps-d), mean = 22.3 tumors/mouse, versus BALB, mean = 13.9 tumors/mouse, difference = 8.4 tumors/mouse, 95% confidence interval = 4.6 to 12.1 tumors/mouse; P = .025) compared with mice with mutated Tlr4 [20].
  • METHODS AND RESULTS: In a femoral artery cuff model in the atherosclerotic ApoE3 (Leiden) transgenic mouse, Tlr4 activation by LPS stimulated plaque formation and subsequent outward arterial remodeling [21].

Associations of Tlr4 with chemical compounds

  • The regulation of the expression of inducible nitric oxide synthase by Src-family tyrosine kinases mediated through MyD88-independent signaling pathways of Toll-like receptor 4 [22].
  • These pathologic changes were significantly lower in TLR4-deficient mice fed ethanol (score = 2.0 +/- 1.3) [23].
  • These results suggest that a common critical molecule, encoded by the Lps gene, regulates both ceramide and LPS signaling pathways [24].
  • The inositol 3-phosphatase PTEN negatively regulates Fc gamma receptor signaling, but supports Toll-like receptor 4 signaling in murine peritoneal macrophages [25].
  • Polymyxin B did not inhibit rTgHSP70- and nTgHSP70-induced tolerance of PMs from TLR4-deficient mice [26].

Physical interactions of Tlr4

  • Induction of macrophage nitric oxide production by Gram-negative flagellin involves signaling via heteromeric Toll-like receptor 5/Toll-like receptor 4 complexes [27].
  • PU.1 binding to the TLR4 promoter was not enhanced in the lung tissue of endotoxin-resistant C3H/HeJ mice in response to endotoxemia [28].
  • The purity of Kdo(2)-Lipid A should facilitate structural analysis of complexes with receptors like TLR-4/MD2 [11].

Regulatory relationships of Tlr4


Other interactions of Tlr4


Analytical, diagnostic and therapeutic context of Tlr4


  1. Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Poltorak, A., He, X., Smirnova, I., Liu, M.Y., Van Huffel, C., Du, X., Birdwell, D., Alejos, E., Silva, M., Galanos, C., Freudenberg, M., Ricciardi-Castagnoli, P., Layton, B., Beutler, B. Science (1998) [Pubmed]
  2. Monoallelic expression of the murine gene encoding Toll-like receptor 4. Pereira, J.P., Girard, R., Chaby, R., Cumano, A., Vieira, P. Nat. Immunol. (2003) [Pubmed]
  3. Overexpression of Toll-like receptor 4 amplifies the host response to lipopolysaccharide and provides a survival advantage in transgenic mice. Bihl, F., Salez, L., Beaubier, M., Torres, D., Larivière, L., Laroche, L., Benedetto, A., Martel, D., Lapointe, J.M., Ryffel, B., Malo, D. J. Immunol. (2003) [Pubmed]
  4. Protective immunity to the larval stages of onchocerca volvulus is dependent on Toll-like receptor 4. Kerepesi, L.A., Leon, O., Lustigman, S., Abraham, D. Infect. Immun. (2005) [Pubmed]
  5. MHCII, Tlr4 and Nramp1 genes control host pulmonary resistance against the opportunistic bacterium Pasteurella pneumotropica. Chapes, S.K., Mosier, D.A., Wright, A.D., Hart, M.L. J. Leukoc. Biol. (2001) [Pubmed]
  6. Down-regulation of mouse organic anion-transporting polypeptide 4 (Oatp4; Oatp1b2; Slc21a10) mRNA by lipopolysaccharide through the toll-like receptor 4 (TLR4). Li, N., Choudhuri, S., Cherrington, N.J., Klaassen, C.D. Drug Metab. Dispos. (2004) [Pubmed]
  7. C5a negatively regulates toll-like receptor 4-induced immune responses. Hawlisch, H., Belkaid, Y., Baelder, R., Hildeman, D., Gerard, C., Köhl, J. Immunity (2005) [Pubmed]
  8. ABIN-2 is required for optimal activation of Erk MAP kinase in innate immune responses. Papoutsopoulou, S., Symons, A., Tharmalingham, T., Belich, M.P., Kaiser, F., Kioussis, D., O'Garra, A., Tybulewicz, V., Ley, S.C. Nat. Immunol. (2006) [Pubmed]
  9. Differential roles of CD14 and toll-like receptors 4 and 2 in murine Acinetobacter pneumonia. Knapp, S., Wieland, C.W., Florquin, S., Pantophlet, R., Dijkshoorn, L., Tshimbalanga, N., Akira, S., van der Poll, T. Am. J. Respir. Crit. Care Med. (2006) [Pubmed]
  10. Bacterially-induced preterm labor and regulation of prostaglandin-metabolizing enzyme expression in mice: the role of toll-like receptor 4. Wang, H., Hirsch, E. Biol. Reprod. (2003) [Pubmed]
  11. Kdo2-Lipid A of Escherichia coli, a defined endotoxin that activates macrophages via TLR-4. Raetz, C.R., Garrett, T.A., Reynolds, C.M., Shaw, W.A., Moore, J.D., Smith, D.C., Ribeiro, A.A., Murphy, R.C., Ulevitch, R.J., Fearns, C., Reichart, D., Glass, C.K., Benner, C., Subramaniam, S., Harkewicz, R., Bowers-Gentry, R.C., Buczynski, M.W., Cooper, J.A., Deems, R.A., Dennis, E.A. J. Lipid Res. (2006) [Pubmed]
  12. Involvement of Toll-like receptor 4 in acetaminophen hepatotoxicity. Yohe, H.C., O'Hara, K.A., Hunt, J.A., Kitzmiller, T.J., Wood, S.G., Bement, J.L., Bement, W.J., Szakacs, J.G., Wrighton, S.A., Jacobs, J.M., Kostrubsky, V., Sinclair, P.R., Sinclair, J.F. Am. J. Physiol. Gastrointest. Liver Physiol. (2006) [Pubmed]
  13. Toll-like receptor 4 on nonhematopoietic cells sustains CNS inflammation during endotoxemia, independent of systemic cytokines. Chakravarty, S., Herkenham, M. J. Neurosci. (2005) [Pubmed]
  14. Endotoxin-tolerant mice have mutations in Toll-like receptor 4 (Tlr4). Qureshi, S.T., Larivière, L., Leveque, G., Clermont, S., Moore, K.J., Gros, P., Malo, D. J. Exp. Med. (1999) [Pubmed]
  15. Corticotropin-releasing factor and the urocortins induce the expression of TLR4 in macrophages via activation of the transcription factors PU.1 and AP-1. Tsatsanis, C., Androulidaki, A., Alissafi, T., Charalampopoulos, I., Dermitzaki, E., Roger, T., Gravanis, A., Margioris, A.N. J. Immunol. (2006) [Pubmed]
  16. Synergistic up-regulation of vascular endothelial growth factor expression in murine macrophages by adenosine A(2A) receptor agonists and endotoxin. Leibovich, S.J., Chen, J.F., Pinhal-Enfield, G., Belem, P.C., Elson, G., Rosania, A., Ramanathan, M., Montesinos, C., Jacobson, M., Schwarzschild, M.A., Fink, J.S., Cronstein, B. Am. J. Pathol. (2002) [Pubmed]
  17. A role for Toll-like receptor 4 in dendritic cell activation and cytolytic CD8+ T cell differentiation in response to a recombinant heat shock fusion protein. Palliser, D., Huang, Q., Hacohen, N., Lamontagne, S.P., Guillen, E., Young, R.A., Eisen, H.N. J. Immunol. (2004) [Pubmed]
  18. Mouse paneth cell secretory responses to cell surface glycolipids of virulent and attenuated pathogenic bacteria. Tanabe, H., Ayabe, T., Bainbridge, B., Guina, T., Ernst, R.K., Darveau, R.P., Miller, S.I., Ouellette, A.J. Infect. Immun. (2005) [Pubmed]
  19. Induction of TNF-alpha and MnSOD by endotoxin: role of membrane CD14 and Toll-like receptor-4. Tsan, M.F., Clark, R.N., Goyert, S.M., White, J.E. Am. J. Physiol., Cell Physiol. (2001) [Pubmed]
  20. Toll-like receptor 4 in butylated hydroxytoluene-induced mouse pulmonary inflammation and tumorigenesis. Bauer, A.K., Dixon, D., DeGraff, L.M., Cho, H.Y., Walker, C.R., Malkinson, A.M., Kleeberger, S.R. J. Natl. Cancer Inst. (2005) [Pubmed]
  21. Toll-like receptor 4 is involved in outward arterial remodeling. Hollestelle, S.C., De Vries, M.R., Van Keulen, J.K., Schoneveld, A.H., Vink, A., Strijder, C.F., Van Middelaar, B.J., Pasterkamp, G., Quax, P.H., De Kleijn, D.P. Circulation (2004) [Pubmed]
  22. The regulation of the expression of inducible nitric oxide synthase by Src-family tyrosine kinases mediated through MyD88-independent signaling pathways of Toll-like receptor 4. Lee, J.Y., Lowell, C.A., Lemay, D.G., Youn, H.S., Rhee, S.H., Sohn, K.H., Jang, B., Ye, J., Chung, J.H., Hwang, D.H. Biochem. Pharmacol. (2005) [Pubmed]
  23. Toll-like receptor 4 is involved in the mechanism of early alcohol-induced liver injury in mice. Uesugi, T., Froh, M., Arteel, G.E., Bradford, B.U., Thurman, R.G. Hepatology (2001) [Pubmed]
  24. Defective ceramide response in C3H/HeJ (Lpsd) macrophages. Barber, S.A., Perera, P.Y., Vogel, S.N. J. Immunol. (1995) [Pubmed]
  25. The inositol 3-phosphatase PTEN negatively regulates Fc gamma receptor signaling, but supports Toll-like receptor 4 signaling in murine peritoneal macrophages. Cao, X., Wei, G., Fang, H., Guo, J., Weinstein, M., Marsh, C.B., Ostrowski, M.C., Tridandapani, S. J. Immunol. (2004) [Pubmed]
  26. Toll-like receptor 4 mediates tolerance in macrophages stimulated with Toxoplasma gondii-derived heat shock protein 70. Mun, H.S., Aosai, F., Norose, K., Piao, L.X., Fang, H., Akira, S., Yano, A. Infect. Immun. (2005) [Pubmed]
  27. Induction of macrophage nitric oxide production by Gram-negative flagellin involves signaling via heteromeric Toll-like receptor 5/Toll-like receptor 4 complexes. Mizel, S.B., Honko, A.N., Moors, M.A., Smith, P.S., West, A.P. J. Immunol. (2003) [Pubmed]
  28. Inducible binding of PU.1 and interacting proteins to the Toll-like receptor 4 promoter during endotoxemia. Pedchenko, T.V., Park, G.Y., Joo, M., Blackwell, T.S., Christman, J.W. Am. J. Physiol. Lung Cell Mol. Physiol. (2005) [Pubmed]
  29. Toxoplasma gondii inhibits toll-like receptor 4 ligand-induced mobilization of intracellular tumor necrosis factor alpha to the surface of mouse peritoneal neutrophils. Bennouna, S., Sukhumavasi, W., Denkers, E.Y. Infect. Immun. (2006) [Pubmed]
  30. TLR4 mediates LPS-induced HO-1 expression in mouse liver: role of TNF-alpha and IL-1beta. Song, Y., Shi, Y., Ao, L.H., Harken, A.H., Meng, X.Z. World J. Gastroenterol. (2003) [Pubmed]
  31. Preterm delivery induced by LPS in syngeneically impregnated BALB/c and NOD/SCID mice. Lin, Y., Xie, M., Chen, Y., Di, J., Zeng, Y. J. Reprod. Immunol. (2006) [Pubmed]
  32. Differential expression and regulation of macrophage inflammatory protein (MIP)-1alpha and MIP-2 genes by alveolar and peritoneal macrophages in LPS-hyporesponsive C3H/HeJ mice. Wang, M.J., Jeng, K.C., Shih, P.C. Cell. Immunol. (2000) [Pubmed]
  33. Lipopolysaccharide-induced down-regulation of organic anion transporting polypeptide 4 (Oatp4; Slc21a10) is independent of tumor necrosis factor-alpha, Interleukin-1beta, interleukin-6, or inducible nitric oxide synthase. Li, N., Klaassen, C.D. Toxicol. Sci. (2005) [Pubmed]
  34. ROS-dependent activation of the TRAF6-ASK1-p38 pathway is selectively required for TLR4-mediated innate immunity. Matsuzawa, A., Saegusa, K., Noguchi, T., Sadamitsu, C., Nishitoh, H., Nagai, S., Koyasu, S., Matsumoto, K., Takeda, K., Ichijo, H. Nat. Immunol. (2005) [Pubmed]
  35. Src homology 2 domain-containing inositol-5-phosphatase 1 (SHIP1) negatively regulates TLR4-mediated LPS response primarily through a phosphatase activity- and PI-3K-independent mechanism. An, H., Xu, H., Zhang, M., Zhou, J., Feng, T., Qian, C., Qi, R., Cao, X. Blood (2005) [Pubmed]
  36. Endogenous interleukin-6, but not tumor necrosis factor alpha, contributes to the development of toll-like receptor 4/myeloid differentiation factor 88-mediated acute arthritis in mice. Kyo, F., Futani, H., Matsui, K., Terada, M., Adachi, K., Nagata, K., Sano, H., Tateishi, H., Tsutsui, H., Nakanishi, K. Arthritis Rheum. (2005) [Pubmed]
  37. Involvement of reactive oxygen species in Toll-like receptor 4-dependent activation of NF-kappa B. Asehnoune, K., Strassheim, D., Mitra, S., Kim, J.Y., Abraham, E. J. Immunol. (2004) [Pubmed]
  38. Toll-like receptor-2, but not Toll-like receptor-4, is essential for development of oviduct pathology in chlamydial genital tract infection. Darville, T., O'Neill, J.M., Andrews, C.W., Nagarajan, U.M., Stahl, L., Ojcius, D.M. J. Immunol. (2003) [Pubmed]
  39. Interleukin 13 gene transfer in liver ischemia and reperfusion injury: role of Stat6 and TLR4 pathways in cytoprotection. Ke, B., Shen, X.D., Gao, F., Busuttil, R.W., Kupiec-Weglinski, J.W. Hum. Gene Ther. (2004) [Pubmed]
  40. TLR4 Is Required for Host Resistance in Pseudomonas aeruginosa Keratitis. Huang, X., Du, W., McClellan, S.A., Barrett, R.P., Hazlett, L.D. Invest. Ophthalmol. Vis. Sci. (2006) [Pubmed]
WikiGenes - Universities