TLR 4

Toll-like receptor 4
	; PDB rendering based on 2z64.
Available structures
PDB	2Z62, 2Z63, 2Z65, 2Z66, 3FXI
Identifiers
Symbols	TLR4; ARMD10; CD284; TOLL
External IDs	OMIM: 603030 MGI: 96824 HomoloGene: 41317 GeneCards: TLR4 Gene
Gene Ontology
Molecular function	• lipopolysaccharide binding; • lipopolysaccharide binding; • lipopolysaccharide receptor activity; • receptor activity; • transmembrane signaling receptor activity; • protein binding; • phosphatidylinositol 3-kinase binding;
Cellular component	• intracellular; • cytoplasm; • plasma membrane; • plasma membrane; • integral to plasma membrane; • external side of plasma membrane; • membrane raft; • lipopolysaccharide receptor complex; • perinuclear region of cytoplasm;
Biological process	• activation of MAPK activity; • response to hypoxia; • toll-like receptor signaling pathway; • microglial cell activation involved in immune response; • nitric oxide production involved in inflammatory response; • MyD88-dependent toll-like receptor signaling pathway; • MyD88-independent toll-like receptor signaling pathway; • innate immune response-activating signal transduction; • skeletal muscle contraction; • immune response; • response to oxidative stress; • signal transduction; • I-kappaB kinase/NF-kappaB cascade; • I-kappaB phosphorylation; • Toll signaling pathway; • response to toxin; • positive regulation of platelet activation; • response to activity; • detection of fungus; • immunoglobulin mediated immune response; • positive regulation of B cell proliferation; • lipopolysaccharide-mediated signaling pathway; • response to lipopolysaccharide; • response to lipopolysaccharide; • detection of lipopolysaccharide; • response to progesterone stimulus; • negative regulation of interferon-gamma production; • negative regulation of interleukin-17 production; • negative regulation of interleukin-23 production; • negative regulation of interleukin-6 production; • negative regulation of tumor necrosis factor production; • positive regulation of chemokine production; • positive regulation of interferon-alpha production; • positive regulation of interferon-beta production; • positive regulation of interferon-gamma production; • positive regulation of interleukin-1 production; • positive regulation of interleukin-10 production; • positive regulation of interleukin-12 production; • positive regulation of interleukin-6 production; • positive regulation of interleukin-8 production; • positive regulation of tumor necrosis factor production; • response to insulin stimulus; • toll-like receptor 1 signaling pathway; • toll-like receptor 2 signaling pathway; • toll-like receptor 4 signaling pathway; • T-helper 1 type immune response; • macrophage activation; • positive regulation of NF-kappaB import into nucleus; • positive regulation of tumor necrosis factor biosynthetic process; • defense response to bacterium; • positive regulation of apoptotic process; • positive regulation of I-kappaB kinase/NF-kappaB cascade; • positive regulation of DNA binding; • positive regulation of interleukin-12 biosynthetic process; • innate immune response; • positive regulation of MHC class II biosynthetic process; • positive regulation of interferon-beta biosynthetic process; • positive regulation of interleukin-8 biosynthetic process; • positive regulation of nitric oxide biosynthetic process; • response to ethanol; • negative regulation of osteoclast differentiation; • positive regulation of transcription from RNA polymerase II promoter; • positive regulation of JNK cascade; • positive regulation of inflammatory response; • positive regulation of peptidyl-tyrosine phosphorylation; • defense response to Gram-negative bacterium; • positive regulation of NF-kappaB transcription factor activity; • positive regulation of nitric-oxide synthase biosynthetic process; • regulation of sensory perception of pain; • pathogen-associated molecular pattern dependent induction by symbiont of host innate immune response; • intestinal epithelial structure maintenance; • positive regulation of macrophage cytokine production; • negative regulation of ERK1 and ERK2 cascade; • positive regulation of ERK1 and ERK2 cascade; • positive regulation of nucleotide-binding oligomerization domain containing 1 signaling pathway; • positive regulation of nucleotide-binding oligomerization domain containing 2 signaling pathway; • response to fatty acid; • cellular response to lipopolysaccharide; • cellular response to lipoteichoic acid; • cellular response to mechanical stimulus;
	Sources: Amigo / QuickGO
RNA expression pattern
	More reference expression data
Orthologs
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Toll-like receptor 4 is a protein that in humans is encoded by the TLR4 gene.^[1]^[2] 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. TLR4 has also been designated as CD284 (cluster of differentiation 284).

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 has been implicated 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. Also, several transcript variants of this gene have been found, but the protein-coding potential of most of them is uncertain.^[3]

Signaling pathway of toll-like receptors. Dashed grey lines represent unknown associations

[edit] Interactions

TLR 4 has been shown to interact with TOLLIP,^[4] Myd88^[5]^[6]^[7]^[8] and Lymphocyte antigen 96.^[9]^[10] Researchers from NTNU has described how 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^[11] . A recent study [3] has 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.^[12]

Toll-like receptor 4 has also 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,^[13]^[14] and in the emergence of side-effects such as hyperalgesia and allodynia that can become a problem following extended use of opioid drugs.^[15]^[16] 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,^[17]^[18] 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.^[19]^[20] 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.^[21])^[20]^[22] This may also be the mechanism behind the beneficial effect of ultra-low dose naltrexone on opioid analgesia.^[23]

[edit] Drugs targeting TLR4

[edit] Agonists

Morphine-3-glucuronide (inactive at opioid receptors, so selective for TLR4 activation)^[16]^[24]
Morphine^[24]
Oxycodone^[24]
Levorphanol^[24]
Pethidine^[24]
Fentanyl^[24]
Methadone^[24]
Buprenorphine^[24]
"Unnatural" isomers such as (+)-morphine activate TLR4 but lack opioid receptor activity,^[19] although (+)-morphine also shows activity as a sigma receptor agonist.^[25]
Lipopolysaccharides (LPS}^[26]
Carbamazepine^[27]
Oxcarbazepine^[27]

[edit] Antagonists

The lipid A analog eritoran acts as a TLR4 antagonist. As of December 2009^[update], it is being developed as a drug against severe sepsis.^[28]
Naloxone^[24]
Naltrexone^[24]
(+)-naloxone ("unnatural" isomer, lacks opioid receptor affinity so selective for TLR4 inhibition)^[20]
(+)-naltrexone^[24]
LPS-RS^[24]
Ibudilast
Propentofylline
Amitriptyline^[27]
Ketotifen^[27]
Cyclobenzaprine^[27]
Mianserin^[27]
Imipramine^[27]

[edit] References

^ Rock FL, Hardiman G, Timans JC, Kastelein RA, Bazan JF (Feb 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. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=18464.
^ Medzhitov R, Preston-Hurlburt P, Janeway CA Jr (Aug 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.
^ "Entrez Gene: TLR4 toll-like receptor 4". http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=7099.
^ Zhang, Guolong; Ghosh Sankar (Mar. 2002). "Negative regulation of toll-like receptor-mediated signaling by Tollip". J. Biol. Chem. (United States) 277 (9): 7059–65. doi:10.1074/jbc.M109537200. ISSN 0021-9258. PMID 11751856.
^ Chuang, Tsung-Hsien; Ulevitch Richard J (May. 2004). "Triad3A, an E3 ubiquitin-protein ligase regulating Toll-like receptors". Nat. Immunol. (United States) 5 (5): 495–502. doi:10.1038/ni1066. ISSN 1529-2908. PMID 15107846.
^ Doyle, Sean E; O'Connell Ryan, Vaidya Sagar A, Chow Edward K, Yee Kathleen, Cheng Genhong (Apr. 2003). "Toll-like receptor 3 mediates a more potent antiviral response than Toll-like receptor 4". J. Immunol. (United States) 170 (7): 3565–71. ISSN 0022-1767. PMID 12646618.
^ Rhee, S H; Hwang D (Nov. 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. (UNITED STATES) 275 (44): 34035–40. doi:10.1074/jbc.M007386200. ISSN 0021-9258. PMID 10952994.
^ Fitzgerald, K A; Palsson-McDermott E M, Bowie A G, Jefferies C A, Mansell A S, Brady G, Brint E, Dunne A, Gray P, Harte M T, McMurray D, Smith D E, Sims J E, Bird T A, O'Neill L A (Sep. 2001). "Mal (MyD88-adapter-like) is required for Toll-like receptor-4 signal transduction". Nature (England) 413 (6851): 78–83. doi:10.1038/35092578. ISSN 0028-0836. PMID 11544529.
^ Re, Fabio; Strominger Jack L (Jun. 2002). "Monomeric recombinant MD-2 binds toll-like receptor 4 tightly and confers lipopolysaccharide responsiveness". J. Biol. Chem. (United States) 277 (26): 23427–32. doi:10.1074/jbc.M202554200. ISSN 0021-9258. PMID 11976338.
^ Shimazu, R; Akashi S, Ogata H, Nagai Y, Fukudome K, Miyake K, Kimoto M (Jun. 1999). "MD-2, a Molecule that Confers Lipopolysaccharide Responsiveness on Toll-like Receptor 4". J. Exp. Med. (UNITED STATES) 189 (11): 1777–82. doi:10.1084/jem.189.11.1777. ISSN 0022-1007. PMC 2193086. PMID 10359581. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2193086.
^ Espevik T, Husebye H, Aune MH, Stenvik J; Samstad E, Skjeldal F, Halaas O, Nilsen NJ, Stenmark H, Latz E, Lien E, Mollnes TE, Bakke O (Oct. 2010). "The Rab11a GTPase controls Toll-like receptor 4-induced activation of interferon regulatory factor-3 on phagosomes". Immunity 33 (4): 583–596. doi:10.1016/j.immuni.2010.09.010. PMID 20933442.
^ Blanco, A. M.; Vallés, S. L.; Pascual, M.; Guerri, C. (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". Journal of immunology (Baltimore, Md. : 1950) 175 (10): 6893–6899. PMID 16272348. edit
^ 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. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2942958.
^ 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.
^ ^a ^b 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. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2795035.
^ Shen CH, Tsai RY, Shih MS et al (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 et al (February 2011). "AN IL-1 RECEPTOR ANTAGONIST BLOCKS A MORPHINE-INDUCED ATTENUATION OF LOCOMOTOR RECOVERY AFTER SPINAL CORD INJURY". Brain, Behavior, and Immunity 25 (2): 349–59. doi:10.1016/j.bbi.2010.10.018. PMC 3025088. PMID 20974246. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=3025088.
^ ^a ^b Watkins LR, Hutchinson MR, Rice KC, Maier SF (November 2009). "The "Toll" of Opioid-Induced Glial Activation: Improving the Clinical Efficacy of Opioids by Targeting Glia". Trends in Pharmacological Sciences 30 (11): 581–91. doi:10.1016/j.tips.2009.08.002. PMC 2783351. PMID 19762094. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2783351.
^ ^a ^b ^c Hutchinson MR, Zhang Y, Brown K, Coats BD, Shridhar M, Sholar PW, Patel SJ, Crysdale NY, Harrison JA, Maier SF, Rice KC, Watkins LR (July 2008). "Non-stereoselective reversal of neuropathic pain by naloxone and naltrexone: involvement of toll-like receptor 4 (TLR4)". The European Journal of Neuroscience 28 (1): 20–9. doi:10.1111/j.1460-9568.2008.06321.x. PMC 2588470. PMID 18662331. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2588470.
^ 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. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2783238.
^ Hutchinson MR, Lewis SS, Coats BD, Rezvani N, Zhang Y, Wieseler JL, Somogyi AA, Yin H, Maier SF, Rice KC, Watkins LR (May 2010). "Possible involvement of Toll-Like Receptor 4/MD-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 2854318. PMID 20178837. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2854318.
^ 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.
^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j ^k ^l Hutchinson MR, Zhang Y, Shridhar M, et al. (January 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 2788078. PMID 19679181. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2788078.
^ Wu HE, Hong JS, Tseng LF (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): 145–51. doi:10.1016/j.ejphar.2007.06.012. PMC 2080825. PMID 17617400. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2080825.
^ 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.
^ ^a ^b ^c ^d ^e ^f ^g 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. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2872682.
^ 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.

[edit] Further reading

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. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2569852.
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.

[edit] External links

MeSH Toll-Like+Receptor+4

[pmid9435236-0] Rock FL, Hardiman G, Timans JC, Kastelein RA, Bazan JF (Feb 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. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=18464.

[pmid9237759-1] Medzhitov R, Preston-Hurlburt P, Janeway CA Jr (Aug 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.

[2] "Entrez Gene: TLR4 toll-like receptor 4". http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=7099.

[pmid11751856-3] Zhang, Guolong; Ghosh Sankar (Mar. 2002). "Negative regulation of toll-like receptor-mediated signaling by Tollip". J. Biol. Chem. (United States) 277 (9): 7059–65. doi:10.1074/jbc.M109537200. ISSN 0021-9258. PMID 11751856.

[pmid15107846-4] Chuang, Tsung-Hsien; Ulevitch Richard J (May. 2004). "Triad3A, an E3 ubiquitin-protein ligase regulating Toll-like receptors". Nat. Immunol. (United States) 5 (5): 495–502. doi:10.1038/ni1066. ISSN 1529-2908. PMID 15107846.

[pmid12646618-5] Doyle, Sean E; O'Connell Ryan, Vaidya Sagar A, Chow Edward K, Yee Kathleen, Cheng Genhong (Apr. 2003). "Toll-like receptor 3 mediates a more potent antiviral response than Toll-like receptor 4". J. Immunol. (United States) 170 (7): 3565–71. ISSN 0022-1767. PMID 12646618.

[pmid10952994-6] Rhee, S H; Hwang D (Nov. 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. (UNITED STATES) 275 (44): 34035–40. doi:10.1074/jbc.M007386200. ISSN 0021-9258. PMID 10952994.

[pmid11544529-7] Fitzgerald, K A; Palsson-McDermott E M, Bowie A G, Jefferies C A, Mansell A S, Brady G, Brint E, Dunne A, Gray P, Harte M T, McMurray D, Smith D E, Sims J E, Bird T A, O'Neill L A (Sep. 2001). "Mal (MyD88-adapter-like) is required for Toll-like receptor-4 signal transduction". Nature (England) 413 (6851): 78–83. doi:10.1038/35092578. ISSN 0028-0836. PMID 11544529.

[pmid11976338-8] Re, Fabio; Strominger Jack L (Jun. 2002). "Monomeric recombinant MD-2 binds toll-like receptor 4 tightly and confers lipopolysaccharide responsiveness". J. Biol. Chem. (United States) 277 (26): 23427–32. doi:10.1074/jbc.M202554200. ISSN 0021-9258. PMID 11976338.

[pmid10359581-9] Shimazu, R; Akashi S, Ogata H, Nagai Y, Fukudome K, Miyake K, Kimoto M (Jun. 1999). "MD-2, a Molecule that Confers Lipopolysaccharide Responsiveness on Toll-like Receptor 4". J. Exp. Med. (UNITED STATES) 189 (11): 1777–82. doi:10.1084/jem.189.11.1777. ISSN 0022-1007. PMC 2193086. PMID 10359581. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2193086.

[pmid20933442-10] Espevik T, Husebye H, Aune MH, Stenvik J; Samstad E, Skjeldal F, Halaas O, Nilsen NJ, Stenmark H, Latz E, Lien E, Mollnes TE, Bakke O (Oct. 2010). "The Rab11a GTPase controls Toll-like receptor 4-induced activation of interferon regulatory factor-3 on phagosomes". Immunity 33 (4): 583–596. doi:10.1016/j.immuni.2010.09.010. PMID 20933442.

[11] Blanco, A. M.; Vallés, S. L.; Pascual, M.; Guerri, C. (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". Journal of immunology (Baltimore, Md. : 1950) 175 (10): 6893–6899. PMID 16272348. edit

[pmid15836969-12] 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.

[pmid20615556-13] 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. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2942958.

[pmid19607972-14] 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.

[pmid19833175-15] 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. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2795035.

[16] Shen CH, Tsai RY, Shih MS et al (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.

[17] Hook MA, Washburn SN, Moreno G et al (February 2011). "AN IL-1 RECEPTOR ANTAGONIST BLOCKS A MORPHINE-INDUCED ATTENUATION OF LOCOMOTOR RECOVERY AFTER SPINAL CORD INJURY". Brain, Behavior, and Immunity 25 (2): 349–59. doi:10.1016/j.bbi.2010.10.018. PMC 3025088. PMID 20974246. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=3025088.

[pmid19762094-18] Watkins LR, Hutchinson MR, Rice KC, Maier SF (November 2009). "The "Toll" of Opioid-Induced Glial Activation: Improving the Clinical Efficacy of Opioids by Targeting Glia". Trends in Pharmacological Sciences 30 (11): 581–91. doi:10.1016/j.tips.2009.08.002. PMC 2783351. PMID 19762094. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2783351.

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