TLR4

TLR4
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
Aliases TLR4, ARMD10, CD284, TLR-4, TOLL, toll like receptor 4
External IDs OMIM: 603030 MGI: 96824 HomoloGene: 41317 GeneCards: TLR4
RNA expression pattern
More reference expression data
Orthologs
Species Human Mouse
Entrez

7099

21898

Ensembl

ENSG00000136869

ENSMUSG00000039005

UniProt

O00206

Q9QUK6

RefSeq (mRNA)

NM_138557
NM_003266
NM_138554
NM_138556

NM_021297

RefSeq (protein)

NP_003257.1
NP_612564.1
NP_612567.1

NP_067272.1

Location (UCSC) Chr 9: 117.7 – 117.72 Mb Chr 4: 66.83 – 66.93 Mb
PubMed search [1] [2]
Wikidata
View/Edit HumanView/Edit Mouse

Toll-like receptor 4 is a protein that in humans is encoded by the TLR4 gene.[3][4] TLR 4 is a toll-like receptor which is responsible for activating the innate immune system. It is most well known for recognizing lipopolysaccharide (LPS), a component present in many Gram-negative bacteria (e.g. Neisseria spp) and select Gram-positive bacteria. Its ligands also include several viral proteins, polysaccharide, and a variety of endogenous proteins such as low-density lipoprotein, beta-defensins, and heat shock protein.[5]

TLR 4 has also been designated as CD284 (cluster of differentiation 284). The molecular weight of TLR 4 is approximately 95 kDa.

Function

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.

The various TLRs exhibit different patterns of expression. This receptor is most abundantly expressed in placenta, and in myelomonocytic subpopulation of the leukocytes.

It cooperates with LY96 (also referred as MD-2) and CD14 to mediate in signal transduction events induced by lipopolysaccharide (LPS)[6] 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.[7]

Evolutionary history

TLR4 originated when TLR2 and TLR4 diverged about 500 million years ago near the beginning of vertebrate evolution.[8] Sequence alignments of human and great ape TLR4 exons have demonstrated that not much evolution has occurred in human TLR4 since our divergence from our last common ancestor with chimpanzees; human and chimp TLR4 exons only differ by three substitutions while humans and baboons are 93.5% similar in the extracellular domain.[9] Notably, humans possess a greater number of early stop codons in TLR4 than great apes; in a study of 158 humans worldwide, 0.6% had a nonsense mutation.[10][11] This suggests that there are weaker evolutionary pressures on the human TLR4 than on our primate relatives. The distribution of human TLR4 polymorphisms matches the out-of-Africa migration, and it is likely that the polymorphisms were generated in Africa before migration to other continents.[11][12]

Interactions

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.[20]

Clinical significance

Various single nucleotide polymorphisms (SNPs) of the TLR4 in humans have been identified[21] and for some of them an association with increased susceptibility to Gram-negative bacterial infections [22] or faster progression and a more severe course of sepsis in critically ill patients was reported.[23]

In pregnancy

Activation of TLR4 in intrauterine infections leads to deregulation of prostaglandin synthesis, leading to uterine smooth muscle contraction.

Asp299Gly polymorphism

Classically, TLR4 is said to be the receptor for LPS, however TLR 4 has also been shown to be activated by other kinds of lipids. Plasmodium falciparum, a parasite known to cause the most common and serious form of malaria that is seen primarily in Africa, produces glycosylphosphatidylinositol, which can activate TLR4.[24] Two SNPs in TLR4 are co-expressed with high penetrance in African populations (i.e. TLR-4-Asp299Gly and TLR-4-Thr399Ile). These Polymorphisms are associated with an increase in TLR4-Mediated IL-10 production—an immunomodulator—and a decrease in proinflammatory cytokines.[25] The TLR-4-Asp299Gly point mutation is strongly correlated with an increased infection rate with Plasmodium falciparum. It appears that the mutation prevents TLR4 from acting as vigorously against, at least some plasmodial infections. The malaria infection rate and associated morbidity are higher in TLR-4-Asp299Gly group, but mortality appears to be decreased. This may indicate that at least part of the pathogenesis of malaria takes advantage of cytokine production. By reducing the cytokine production via the TLR4 mutation, the infection rate may increase, but the number of deaths due to the infection seem to decrease.[24]

In addition, TLR4-D299G has been associated with aggressive colorectal cancer in humans. It has been shown that human colon adenocarcinomas from patients with TLR4-D299G were more frequently of an advanced stage with metastasis than those with wild-type TLR4. The same study demonstrated functionally that intestinal epithelial cells (Caco-2) expressing TLR4-D299G underwent epithelial-mesenchymal transition and morphologic changes associated with tumor progression, whereas intestinal epithelial cells expressing wild-type TLR4 did not.[26]

Animal studies

A link between the TLR 4 receptor and binge drinking has been suggested. When genes responsible for the expression of TLR 4 and GABA receptors are manipulated in rodents that had been bred and trained to drink excessively, the animals showed a "profound reduction" in drinking behaviours.[27] Additionally, it has been shown that ethanol, even in the absence of LPS, can activate TLR4 signaling pathways.[28]

High levels of TLR4 molecules and M2 tumor-associated macrophages are associated with 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.[29]

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,[30][31] and in the emergence of side-effects such as hyperalgesia and allodynia that can become a problem following extended use of opioid drugs.[32][33] 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,[34][35] 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.[36][37] 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.[38])[37][39] This may also be the mechanism behind the beneficial effect of ultra-low dose naltrexone on opioid analgesia.[40]

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).[41] The morphine-induced TLR4 activation attenuates pain suppression by opioids and enhances the development of opioid tolerance and addiction, drug abuse, and other negative side effects such as respiratory depression and hyperalgesia. Drug candidates that target TLR4 may improve opioid-based pain management therapies.[42]

Agonists

Antagonists

References

  1. ↑ "Human PubMed Reference:".
  2. ↑ "Mouse PubMed Reference:".
  3. ↑ 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 18464Freely accessible. PMID 9435236.
  4. ↑ Medzhitov R, Preston-Hurlburt P, Janeway CA (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.
  5. ↑ Brubaker SW, Bonham KS, Zanoni I, Kagan JC (2015). "Innate immune pattern recognition: a cell biological perspective". Annual Review of Immunology. 33: 257–90. doi:10.1146/annurev-immunol-032414-112240. PMID 25581309.
  6. ↑ "O00206 (TLR4_HUMAN)". Uniprot.
  7. ↑ "Entrez Gene: TLR 4 toll-like receptor 4".
  8. ↑ Beutler B, Rehli M (2002). "Evolution of the TIR, tolls and TLRs: functional inferences from computational biology". Current Topics in Microbiology and Immunology. 270: 1–21. PMID 12467241.
  9. ↑ Smirnova I, Poltorak A, Chan EK, McBride C, Beutler B (2000). "Phylogenetic variation and polymorphism at the toll-like receptor 4 locus (TLR4)". Genome Biology. 1 (1): RESEARCH002. doi:10.1186/gb-2000-1-1-research002. PMID 11104518.
  10. ↑ Quach H, Wilson D, Laval G, Patin E, Manry J, Guibert J, Barreiro LB, Nerrienet E, Verschoor E, Gessain A, Przeworski M, Quintana-Murci L (Dec 2013). "Different selective pressures shape the evolution of Toll-like receptors in human and African great ape populations". Human Molecular Genetics. 22 (23): 4829–40. doi:10.1093/hmg/ddt335. PMID 23851028.
  11. 1 2 Barreiro LB, Ben-Ali M, Quach H, Laval G, Patin E, Pickrell JK, Bouchier C, Tichit M, Neyrolles O, Gicquel B, Kidd JR, Kidd KK, Alcaïs A, Ragimbeau J, Pellegrini S, Abel L, Casanova JL, Quintana-Murci L (Jul 2009). "Evolutionary dynamics of human Toll-like receptors and their different contributions to host defense". PLoS Genetics. 5 (7): e1000562. doi:10.1371/journal.pgen.1000562. PMC 2702086Freely accessible. PMID 19609346.
  12. ↑ Plantinga TS, Ioana M, Alonso S, Izagirre N, Hervella M, Joosten LA, van der Meer JW, de la Rúa C, Netea MG (2012). "The evolutionary history of TLR4 polymorphisms in Europe". Journal of Innate Immunity. 4 (2): 168–75. doi:10.1159/000329492. PMID 21968286.
  13. ↑ 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.
  14. ↑ 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 2193086Freely accessible. PMID 10359581.
  15. ↑ 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.
  16. ↑ 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.
  17. ↑ 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.
  18. ↑ 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.
  19. ↑ 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.
  20. ↑ 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.
  21. ↑ Schröder NW, Schumann RR (2005). "Single nucleotide polymorphisms of Toll-like receptors and susceptibility to infectious disease.". Lancet Infect Dis. 5 (3): 156–64. doi:10.1016/S1473-3099(05)01308-3. PMID 15766650.
  22. ↑ Lorenz E, Mira JP, Frees KL, Schwartz DA (2002). "Relevance of mutations in the TLR4 receptor in patients with gram-negative septic shock.". Arch Intern Med. 162 (9): 1028–32. doi:10.1001/archinte.162.9.1028. PMID 11996613.
  23. ↑ Nachtigall I, Tamarkin A, Tafelski S, Weimann A, Rothbart A, Heim S, Wernecke KD, Spies C (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.
  24. 1 2 Mockenhaupt FP, Cramer JP, Hamann L, Stegemann MS, Eckert J, Oh NR, Otchwemah RN, Dietz E, Ehrhardt S, Schröder NW, Bienzle U, Schumann RR (Jan 2006). "Toll-like receptor (TLR) polymorphisms in African children: Common TLR-4 variants predispose to severe malaria". Proceedings of the National Academy of Sciences of the United States of America. 103 (1): 177–82. doi:10.1073/pnas.0506803102. PMID 16371473.
  25. ↑ Van der Graaf CA, Netea MG, Morré SA, Den Heijer M, Verweij PE, Van der Meer JW, Kullberg BJ (Mar 2006). "Toll-like receptor 4 Asp299Gly/Thr399Ile polymorphisms are a risk factor for Candida bloodstream infection". European Cytokine Network. 17 (1): 29–34. PMID 16613760.
  26. ↑ Eyking A, Ey B, Rünzi M, Roig AI, Reis H, Schmid KW, Gerken G, Podolsky DK, Cario E (December 2011). "Toll-like receptor 4 variant D299G induces features of neoplastic progression in Caco-2 intestinal cells and is associated with advanced human colon cancer". Gastroenterology. 141 (6): 2154–65. doi:10.1053/j.gastro.2011.08.043. PMC 3268964Freely accessible. PMID 21920464.
  27. ↑ Liu J, Yang AR, Kelly T, Puche A, Esoga C, June HL, Elnabawi A, Merchenthaler I, Sieghart W, June HL, Aurelian L (2011). "Binge alcohol drinking is associated with GABAA alpha2-regulated Toll-like receptor 4 (TLR4) expression in the central amygdala". Proc. Natl. Acad. Sci. U.S.A. 108 (11): 4465–70. doi:10.1073/pnas.1019020108. PMC 3060224Freely accessible. PMID 21368176. Lay summary – sciencedaily.com.
  28. ↑ 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. doi:10.4049/jimmunol.175.10.6893. PMID 16272348.
  29. ↑ Hakim F, Wang Y, Zhang SX, Zheng J, Yolcu ES, 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 Res. 74 (5): 1329–37. doi:10.1158/0008-5472.CAN-13-3014. PMID 24448240.
  30. ↑ 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.
  31. ↑ 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 2942958Freely accessible. PMID 20615556.
  32. ↑ 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.
  33. 1 2 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 2795035Freely accessible. PMID 19833175.
  34. ↑ 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.
  35. ↑ 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 3025088Freely accessible. PMID 20974246.
  36. 1 2 Watkins LR, Hutchinson MR, Rice KC, Maier SF (2009). "The "toll" of opioid-induced glial activation: improving the clinical efficacy of opioids by targeting glia". Trends Pharmacol. Sci. 30 (11): 581–91. doi:10.1016/j.tips.2009.08.002. PMC 2783351Freely accessible. PMID 19762094.
  37. 1 2 3 Hutchinson MR, Zhang Y, Brown K, Coats BD, Shridhar M, Sholar PW, Patel SJ, Crysdale NY, Harrison JA, Maier SF, Rice KC, Watkins LR (2008). "Non-stereoselective reversal of neuropathic pain by naloxone and naltrexone: involvement of toll-like receptor 4 (TLR4)". Eur. J. Neurosci. 28 (1): 20–9. doi:10.1111/j.1460-9568.2008.06321.x. PMC 2588470Freely accessible. PMID 18662331.
  38. ↑ 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 2783238Freely accessible. PMID 18599265.
  39. ↑ Hutchinson MR, Lewis SS, Coats BD, Rezvani N, Zhang Y, Wieseler JL, Somogyi AA, Yin H, Maier SF, Rice KC, Watkins LR (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): 880–93. doi:10.1016/j.neuroscience.2010.02.011. PMC 2854318Freely accessible. PMID 20178837.
  40. ↑ 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.
  41. ↑ "Neuroscience: Making morphine work better". Nature. 484 (7395): 419. 26 April 2012. doi:10.1038/484419a.
  42. ↑ Drahl C (22 August 2012). "Small Molecules Target Toll-Like Receptors". Chemical & Engineering News.
  43. 1 2 3 4 5 6 7 8 9 10 11 12 Hutchinson MR, Zhang Y, Shridhar M, Evans JH, Buchanan MM, Zhao TX, Slivka PF, Coats BD, Rezvani N, Wieseler J, Hughes TS, Landgraf KE, Chan S, Fong S, Phipps S, Falke JJ, Leinwand LA, Maier SF, Yin H, Rice KC, Watkins LR (2010). "Evidence that opioids may have toll-like receptor 4 and MD-2 effects". Brain Behav. Immun. 24 (1): 83–95. doi:10.1016/j.bbi.2009.08.004. PMC 2788078Freely accessible. PMID 19679181.
  44. 1 2 3 4 5 6 7 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 2872682Freely accessible. PMID 20381591.
  45. ↑ 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.
  46. ↑ 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.
  47. ↑ 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.
  48. ↑ 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.
  49. ↑ Wu HE, Hong JS, Tseng LF (2007). "Stereoselective action of (+)-morphine over (-)-morphine in attenuating the (-)-morphine-produced antinociception via the naloxone-sensitive sigma receptor in the mouse". Eur. J. Pharmacol. 571 (2-3): 145–51. doi:10.1016/j.ejphar.2007.06.012. PMC 2080825Freely accessible. PMID 17617400.
  50. ↑ 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.
  51. ↑ "New drug offers novel approach to taming flu virus - Vitals". NBCNews. 1 May 2013.
  52. ↑ Jia ZJ, Wu FX, Huang QH, Liu JM (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. PMID 22776604.
Signaling pathway of toll-like receptors. Dashed grey lines represent unknown associations

Further reading

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