|Toll-like receptor 4|
PDB rendering based on 2z64.
|Symbols||; ARMD10; CD284; TLR-4; TOLL|
|External IDs||ChEMBL: GeneCards:|
|RNA expression pattern|
Toll-like receptor 4 is a protein that in humans is encoded by the TLR4 gene. TLR 4 is a toll-like receptor. It detects lipopolysaccharide from Gram-negative bacteria and is thus important in the activation of the innate immune system. TLR 4 has also been designated as CD284 (cluster of differentiation 284). The molecular weight of TLR 4 is approximately 95 kDa.
The protein encoded by this gene is a member of the Toll-like receptor (TLR) family, which plays a fundamental role in pathogen recognition and activation of innate immunity. TLRs are highly conserved from Drosophila to humans and share structural and functional similarities. They recognize pathogen-associated molecular patterns (PAMPs) that are expressed on infectious agents, and mediate the production of cytokines necessary for the development of effective immunity.
It cooperates with LY96 and CD14 to mediate in signal transduction events induced by lipopolysaccharide (LPS) found in most gram-negative bacteria. Mutations in this gene have been associated with differences in LPS responsiveness.
Several transcript variants of this gene have been found, but the protein-coding potential of most of them is uncertain.
TLR 4 has been shown to interact with:
Intracellular trafficking of TLR4 is dependent on the GTPase Rab-11a, and knock down of Rab-11a results in hampered TLR4 recruitment to E. coli-containing phagosomes and subsequent reduced signal transduction through the MyD88-independent pathway.
A 2005 study  suggested a link between the TLR 4 receptor and binge drinking; when researchers manipulated the genes responsible for the expression of TLR 4 and GABA receptors in rodents that had been bred and trained to drink excessively, the animals showed a "profound reduction" in drinking behaviours. Additionally, it has been shown that ethanol, even in the absence of LPS, can activate TLR4 signaling pathways.
Various single nucleotide polymorphisms (SNPs) of the TLR4 in humans have been identified and for some of them an association with increased susceptibility to Gram-negative bacterial infections or faster progression and a more severe course of sepsis in critically ill patients was reported. 
A 2014 study found high levels of TLR4 molecules and M2 tumor-associated macrophages and increased susceptibility to cancer growth in mice deprived of sleep. Mice genetically modified so that they could not produce TLR4 molecules showed normal cancer growth.
Drugs targeting TLR4
Toll-like receptor 4 has been shown to be important for the long-term side-effects of opioid analgesic drugs. Various μ-opioid receptor ligands have been tested and found to also possess action as agonists or antagonists of TLR4, with opioid agonists such as morphine being TLR4 agonists, while opioid antagonists such as naloxone were found to be TLR4 antagonists. Activation of TLR4 leads to downstream release of inflammatory modulators including TNF-α and Interleukin-1, and constant low-level release of these modulators is thought to reduce the efficacy of opioid drug treatment with time, and be involved in both the development of tolerance to opioid analgesic drugs, and in the emergence of side-effects such as hyperalgesia and allodynia that can become a problem following extended use of opioid drugs. Drugs that block the action of TNF-α or IL-1β have been shown to increase the analgesic effects of opioids and reduce the development of tolerance and other side-effects, and this has also been demonstrated with drugs that block TLR4 itself. Interestingly the response of TLR4 to opioid drugs has been found to be enantiomer-independent, so the "unnatural" enantiomers of opioid drugs such as morphine and naloxone, which lack affinity for opioid receptors, still produce the same activity at TLR4 as their "normal" enantiomers. This means that the unnatural enantiomers of opioid antagonists, such as (+)-naloxone, can be used to block the TLR4 activity of opioid analgesic drugs, while leaving the μ-opioid receptor mediated analgesic activity unaffected.) This may also be the mechanism behind the beneficial effect of ultra-low dose naltrexone on opioid analgesia.
Morphine causes inflammation by binding to the protein lymphocyte antigen 96, which, in turn, causes the protein to bind to Toll-like receptor 4 (TLR4). The morphine-induced TLR4 activation attenuates pain suppression by opioid and enhances the development of opioid tolerance and addiction, drug abuse, and other negative side effects such as respiratory depression. Drug candidates that target TLR4 may improve opioid-based pain management therapies.
- Morphine-3-glucuronide (inactive at opioid receptors, so selective for TLR4 activation)
- Glucuronoxylomannan from Cryptococcus
- "Unnatural" isomers such as (+)-morphine activate TLR4 but lack opioid receptor activity, although (+)-morphine also shows activity as a sigma receptor agonist.
- Lipopolysaccharides (LPS)
- The lipid A analog eritoran acts as a TLR4 antagonist. As of December 2009[update], it was being developed as a drug against severe sepsis. However, in 2013, a news story said the results against sepsis were somewhat disappointing and that it was better used to treat certain cases of severe influenza, though it does not treat the virus itself but against the massive immune reaction called cytokine storm which occurs later in the infection and, sometimes in concert with sepsis (it can also help cause sepsis), sometimes alone, can kill.
- (+)-naloxone ("unnatural" isomer, lacks opioid receptor affinity so selective for TLR4 inhibition)
- Propentofylline
- Rock FL, Hardiman G, Timans JC, Kastelein RA, Bazan JF (February 1998). "A family of human receptors structurally related to Drosophila Toll". Proc Natl Acad Sci U S A 95 (2): 588–93. doi:10.1073/pnas.95.2.588. PMC 18464. PMID 9435236.
- Medzhitov R, Preston-Hurlburt P, Janeway CA Jr (August 1997). "A human homologue of the Drosophila Toll protein signals activation of adaptive immunity". Nature 388 (6640): 394–7. doi:10.1038/41131. PMID 9237759.
- "O00206 (TLR4_HUMAN)". Uniprot.
- "Entrez Gene: TLR 4 toll-like receptor 4".
- Re F, Strominger JL (June 2002). "Monomeric recombinant MD-2 binds toll-like receptor 4 tightly and confers lipopolysaccharide responsiveness". J. Biol. Chem. 277 (26): 23427–32. doi:10.1074/jbc.M202554200. PMID 11976338.
- Shimazu R, Akashi S, Ogata H, Nagai Y, Fukudome K, Miyake K, Kimoto M (June 1999). "MD-2, a molecule that confers lipopolysaccharide responsiveness on Toll-like receptor 4". J. Exp. Med. 189 (11): 1777–82. doi:10.1084/jem.189.11.1777. PMC 2193086. PMID 10359581.
- Chuang TH, Ulevitch RJ (May 2004). "Triad3A, an E3 ubiquitin-protein ligase regulating Toll-like receptors". Nat. Immunol. 5 (5): 495–502. doi:10.1038/ni1066. PMID 15107846.
- Doyle SE, O'Connell R, Vaidya SA, Chow EK, Yee K, Cheng G (April 2003). "Toll-like receptor 3 mediates a more potent antiviral response than Toll-like receptor 4". J. Immunol. 170 (7): 3565–71. doi:10.4049/jimmunol.170.7.3565. PMID 12646618.
- Rhee SH, Hwang D (November 2000). "Murine TOLL-like receptor 4 confers lipopolysaccharide responsiveness as determined by activation of NF kappa B and expression of the inducible cyclooxygenase". J. Biol. Chem. 275 (44): 34035–40. doi:10.1074/jbc.M007386200. PMID 10952994.
- Fitzgerald KA, Palsson-McDermott EM, Bowie AG, Jefferies CA, Mansell AS, Brady G, Brint E, Dunne A, Gray P, Harte MT, McMurray D, Smith DE, Sims JE, Bird TA, O'Neill LA (September 2001). "Mal (MyD88-adapter-like) is required for Toll-like receptor-4 signal transduction". Nature 413 (6851): 78–83. doi:10.1038/35092578. PMID 11544529.
- Zhang G, Ghosh S (March 2002). "Negative regulation of toll-like receptor-mediated signaling by Tollip". J. Biol. Chem. 277 (9): 7059–65. doi:10.1074/jbc.M109537200. PMID 11751856.
- Husebye H, Aune MH, Stenvik J, Samstad E, Skjeldal F, Halaas O, Nilsen NJ, Stenmark H, Latz E, Lien E, Mollnes TE, Bakke O, Espevik T (October 2010). "The Rab11a GTPase controls Toll-like receptor 4-induced activation of interferon regulatory factor-3 on phagosomes". Immunity 33 (4): 583–96. doi:10.1016/j.immuni.2010.09.010. PMID 20933442.
- Blanco AM, Vallés SL, Pascual M, Guerri C (November 2005). "Involvement of TLR4/type I IL-1 receptor signaling in the induction of inflammatory mediators and cell death induced by ethanol in cultured astrocytes". J. Immunol. 175 (10): 6893–9. PMID 16272348.
- Schroder NW (2005). "Single nucleotide polymorphisms of Toll-like receptors and susceptibility to infectious disease.". Lancet Infect Dis. PMID 15766650.
- Lorenz E (2002). "Relevance of mutations in the TLR4 receptor in patients with gram-negative septic shock.". Arch Intern Med. PMID 11996613.
- Nachtigall I (Feb 2014). "Polymorphisms of the toll-like receptor 2 and 4 genes are associated with faster progression and a more severe course of sepsis in critically ill patients.". J Int Med Res 42 (1): 93–110. doi:10.1177/0300060513504358. PMID 24366499.
- Hakim, F.; Wang, Y.; Zhang, S. X. L.; Zheng, J.; Yolcu, E. S.; Carreras, A.; Khalyfa, A.; Shirwan, H.; Almendros, I.; Gozal, D. (2014). "Fragmented Sleep Accelerates Tumor Growth and Progression through Recruitment of Tumor-Associated Macrophages and TLR4 Signaling". Cancer Research 74 (5): 1329. doi:10.1158/0008-5472.CAN-13-3014. PMID 24448240.
- Shavit Y, Wolf G, Goshen I, Livshits D, Yirmiya R (May 2005). "Interleukin-1 antagonizes morphine analgesia and underlies morphine tolerance". Pain 115 (1–2): 50–9. doi:10.1016/j.pain.2005.02.003. PMID 15836969.
- Mohan S, Davis RL, DeSilva U, Stevens CW (October 2010). "Dual regulation of mu opioid receptors in SK-N-SH neuroblastoma cells by morphine and interleukin-1β: evidence for opioid-immune crosstalk". Journal of Neuroimmunology 227 (1–2): 26–34. doi:10.1016/j.jneuroim.2010.06.007. PMC 2942958. PMID 20615556.
- Komatsu T, Sakurada S, Katsuyama S, Sanai K, Sakurada T (2009). "Mechanism of allodynia evoked by intrathecal morphine-3-glucuronide in mice". International Review of Neurobiology. International Review of Neurobiology 85: 207–19. doi:10.1016/S0074-7742(09)85016-2. ISBN 9780123748935. PMID 19607972.
- Lewis SS, Hutchinson MR, Rezvani N, Loram LC, Zhang Y, Maier SF, Rice KC, Watkins LR (January 2010). "Evidence that intrathecal morphine-3-glucuronide may cause pain enhancement via toll-like receptor 4/MD-2 and interleukin-1β". Neuroscience 165 (2): 569–83. doi:10.1016/j.neuroscience.2009.10.011. PMC 2795035. PMID 19833175.
- Shen CH, Tsai RY, Shih MS, Lin SL, Tai YH, Chien CC, Wong CS (February 2011). "Etanercept restores the antinociceptive effect of morphine and suppresses spinal neuroinflammation in morphine-tolerant rats". Anesth. Analg. 112 (2): 454–9. doi:10.1213/ANE.0b013e3182025b15. PMID 21081778.
- Hook MA, Washburn SN, Moreno G, Woller SA, Puga D, Lee KH, Grau JW (February 2011). "An IL-1 receptor antagonist blocks a morphine-induced attenuation of locomotor recovery after spinal cord injury". Brain Behav. Immun. 25 (2): 349–59. doi:10.1016/j.bbi.2010.10.018. PMC 3025088. PMID 20974246.
- Watkins, Linda R.; Hutchinson, Mark R.; Rice, Kenner C.; Maier, Steven F. (2009). "The "Toll" of Opioid-Induced Glial Activation: Improving the Clinical Efficacy of Opioids by Targeting Glia". Trends in Pharmacological Sciences 30 (11): 581–591. doi:10.1016/j.tips.2009.08.002. PMC 2783351. PMID 19762094.
- Hutchinson, Mark R.; Zhang, Yingning; Brown, Kimberley; Coats, Benjamen D.; Shridhar, Mitesh; Sholar, Paige W.; Patel, Sonica J.; Crysdale, Nicole Y.; Harrison, Jacqueline A.; Maier, Steven F.; Rice, Kenner C.; Watkins, Linda R. (July 2008). "Non-stereoselective reversal of neuropathic pain by naloxone and naltrexone: involvement of toll-like receptor 4 (TLR4)". European Journal of Neuroscience 28 (1): 20–29. doi:10.1111/j.1460-9568.2008.06321.x. PMC 2588470. PMID 18662331.
- Hutchinson MR, Coats BD, Lewis SS, Zhang Y, Sprunger DB, Rezvani N, Baker EM, Jekich BM, Wieseler JL, Somogyi AA, Martin D, Poole S, Judd CM, Maier SF, Watkins LR (November 2008). "Proinflammatory cytokines oppose opioid induced acute and chronic analgesia". Brain, Behavior, and Immunity 22 (8): 1178–89. doi:10.1016/j.bbi.2008.05.004. PMC 2783238. PMID 18599265.
- Hutchinson, Mark R.; Lewis, S. S.; Coats, Benjamen D.; Rezvani, Niloofar; Zhang, Y.; Wieseler, Julie L.; Somogyi, A. A.; Yin, Hang; Maier, Steven F.; Rice, Kenner C.; Watkins, Linda R. (19 May 2010). "Possible involvement of toll-like receptor 4/myeloid differentiation factor-2 activity of opioid inactive isomers causes spinal proinflammation and related behavioral consequences". Neuroscience 167 (3): 880–893. doi:10.1016/j.neuroscience.2010.02.011. PMC 2854318. PMID 20178837.
- Lin SL, Tsai RY, Tai YH, Cherng CH, Wu CT, Yeh CC, Wong CS (February 2010). "Ultra-low dose naloxone upregulates interleukin-10 expression and suppresses neuroinflammation in morphine-tolerant rat spinal cords". Behavioural Brain Research 207 (1): 30–6. doi:10.1016/j.bbr.2009.09.034. PMID 19799935.
- "Nature news coverage".
- "C&EN News coverage".
- Pascual M, Baliño P, Alfonso-Loeches S, Aragón CM, Guerri C (June 2011). "Impact of TLR4 on behavioral and cognitive dysfunctions associated with alcohol-induced neuroinflammatory damage". Brain Behav. Immun. 25 Suppl 1: S80–91. doi:10.1016/j.bbi.2011.02.012. PMID 21352907.
- Hutchinson, Mark R.; Zhang, Yingning; Shridhar, Mitesh; Evans, John H.; Buchanan, Madison M.; Zhao, Tina X.; Slivka, Peter F.; Coats, Benjamen D.; Rezvani, Niloofar; Wieseler, Julie; Hughes, Travis S.; Landgraf, Kyle E.; Chan, Stefanie; Fong, Stephanie; Phipps, Simon; Falke, Joseph J.; Leinwand, Leslie A.; Maier, Steven F.; Yin, Hang; Rice, Kenner C.; Watkins, Linda R. (2010). "Evidence that opioids may have toll-like receptor 4 and MD-2 effects". Brain, Behavior, and Immunity 24: 83–95. doi:10.1016/j.bbi.2009.08.004. PMC 2788078. PMID 19679181.
- Harris SA, Solomon KR (July 1992). "Percutaneous penetration of 2,4-dichlorophenoxyacetic acid and 2,4-D dimethylamine salt in human volunteers". J Toxicol Environ Health 36 (3): 233–40. doi:10.1080/15287399209531634. PMID 1629934.
- Monari C, Bistoni F, Casadevall A, Pericolini E, Pietrella D, Kozel TR, Vecchiarelli A (January 2005). "Glucuronoxylomannan, a microbial compound, regulates expression of costimulatory molecules and production of cytokines in macrophages". J. Infect. Dis. 191 (1): 127–37. doi:10.1086/426511. PMID 15593014.
- Wu, Hsiang-en; Hong, Jau-Shyong; Tseng, Leon F. (1 October 2007). "Stereoselective action of (+)-morphine over (−)-morphine in attenuating the (−)-morphine-produced antinociception via the naloxone-sensitive sigma receptor in the mouse". European Journal of Pharmacology 571 (2–3): 145–151. doi:10.1016/j.ejphar.2007.06.012. PMC 2080825. PMID 17617400.
- Kelley KW, Dantzer R (June 2011). "Alcoholism and inflammation: neuroimmunology of behavioral and mood disorders". Brain Behav. Immun. 25 Suppl 1: S13–20. doi:10.1016/j.bbi.2010.12.013. PMID 21193024.
- Hutchinson MR, Loram LC, Zhang Y, Shridhar M, Rezvani N, Berkelhammer D, Phipps S, Foster PS, Landgraf K, Falke JJ, Rice KC, Maier SF, Yin H, Watkins LR (June 2010). "Evidence that tricyclic small molecules may possess Toll-like receptor and MD-2 activity". Neuroscience 168 (2): 551–63. doi:10.1016/j.neuroscience.2010.03.067. PMC 2872682. PMID 20381591.
- Tidswell, M; Tillis, W; Larosa, SP; Lynn, M; Wittek, AE; Kao, R; Wheeler, J; Gogate, J et al. (2010). "Phase 2 trial of eritoran tetrasodium (E5564), a Toll-like receptor 4 antagonist, in patients with severe sepsis". Critical Care Medicine 38 (1): 72–83. doi:10.1097/CCM.0b013e3181b07b78. PMID 19661804.
- Ze-Jun J, Fei-Xiang W, Qing-Hai H, Jian-Min L (April 2012). "Toll-like Receptor 4: The Potential Therapeutic Target for Neuropathic Pain". Zhongguo Yi Xue Ke Xue Yuan Xue Bao 34 (2): 168–73. doi:10.3881/j.issn.1000-503X.2012.02.013 (inactive 2014-03-24). PMID 22776604.
- Lien E, Ingalls RR (2002). "Toll-like receptors". Crit. Care Med. 30 (1 Suppl): S1–11. doi:10.1097/00003246-200201001-00001. PMID 11782555.
- Raetz CR, Whitfield C (2002). "Lipopolysaccharide Endotoxins". Annu. Rev. Biochem. 71: 635–700. doi:10.1146/annurev.biochem.71.110601.135414. PMC 2569852. PMID 12045108.
- Lin WJ, Yeh WC (2005). "Implication of Toll-like receptor and tumor necrosis factor alpha signaling in septic shock". Shock 24 (3): 206–9. doi:10.1097/01.shk.0000180074.69143.77. PMID 16135957.
- Lorenz E (2007). "TLR2 and TLR4 expression during bacterial infections". Curr. Pharm. Des. 12 (32): 4185–93. doi:10.2174/138161206778743547. PMID 17100621.
- Stoll LL, Denning GM, Weintraub NL (2007). "Endotoxin, TLR4 signaling and vascular inflammation: potential therapeutic targets in cardiovascular disease". Curr. Pharm. Des. 12 (32): 4229–45. doi:10.2174/138161206778743501. PMID 17100625.
- Rousseaux C, Desreumaux P (2007). "[The peroxisome-proliferator-activated gamma receptor and chronic inflammatory bowel disease (PPARgamma and IBD)]". J. Soc. Biol. 200 (2): 121–31. doi:10.1051/jbio:2006015. PMID 17151549.
- Szabo G, Dolganiuc A, Dai Q, Pruett SB (2007). "TLR4, ethanol, and lipid rafts: a new mechanism of ethanol action with implications for other receptor-mediated effects". J. Immunol. 178 (3): 1243–9. PMID 17237368.