Toll様受容体4

関: Toll-like receptor 4

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2012/11/16 08:22:06」(JST)

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TLR4の構造

TLR4（Toll様受容体4、英：Toll-like receptor 4）は病原体に特徴的な分子を認識するToll様受容体の1つで、グラム陰性菌の外膜の成分であるリポ多糖（LPS）やグラム陽性菌のペプチドグリカン層にあるリポテイコ酸をリガンドとして認識する受容体である。通常の免疫反応に関わる一方で、リガンドが多すぎる場合には細菌性ショック（敗血症）を起こしうる。

TLR4のシグナル伝達経路

リガンドの認識機構

TLR4はもともとリポ多糖（LPS）を認識する受容体としてその機能が同定されたものである。血中のリポ多糖はまず、肝臓で作られるリポ多糖結合タンパク質（LPS binding protein: LBP）と結合した後、細胞膜上のCD14に運ばれる。そしてCD14からTLR4とMD2の複合体に受け渡される時にTLR4が二量体となり細胞内にシグナルが伝わる。このシグナル経路ではまず、TLR4の細胞内側にあるTIRドメインにアダプター分子であるMyD88が結合する。MyD88はデスドメインを介してIRAKに結合してこれを活性化し、TRAF6をリン酸化する。このTRAF6がMAPKKK（MAPキナーゼキナーゼキナーゼ）であるTAK1を活性化するので、MAPキナーゼ経路の活性化やNF-κBの活性化を導く。あるいは、TLR4は同じくTIRドメインを介してTRIFを活性化しインターフェロンの制御因子であるIRF3を活性化する。このように、NF-κBやIRFといった転写因子を発現することで、活性化したマクロファージなどはIFN-γやTNF-αといったサイトカインを分泌する一方、樹状細胞ではCCR7というケモカイン受容体の発現を強めてケモカインCCL21に対する感受性を高める。ここにケモカインがくるとMHCクラスI・II分子や補助刺激分子B7（CD80・CD86）の発現が誘導される。

機能

TLR4はB細胞において、T細胞に依存しない活性化を行うことができる。すなわち、通常のB細胞は抗原のペプチド断片を認識したT細胞によって同じ抗原を認識するB細胞が活性化されるのであるが、リポ多糖に結合できるBCR（B細胞受容体）をもつB細胞（すなわち、リポ多糖を抗原として認識できてそれに対する抗体を作りえるB細胞）のTLR4にリポ多糖が結合すると、BCRとTLR4の両方からシグナルが入り増殖・分化が促される（このとき、リポ多糖に結合できるBCRを持たないB細胞はあまり活性化しない）。しかし、細菌の大量死により多量のリポ多糖が放出されると、リポ多糖に結合できるBCRを持たないB細胞も活性化されるので、過剰なサイトカイン（TNF-αなど）の放出などの免疫系の錯乱が起こる。これがひどい場合には細菌性ショック（敗血症）を起こす。

TLR4を標的とした薬剤

LPSの構成成分リピドAのアナログであるエリトランは、TLR4のアンタゴニストであり敗血症の治療薬として治験が行われている^[1]^[2]。

脚注

^ Tidswell M, Tillis W, Larosa SP, Lynn M, Wittek AE, Kao R, Wheeler J, Gogate J, Opal SM; Eritoran Sepsis Study Group (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.
^ エーザイ (2010年3月26日). “重症敗血症治療剤「エリトラン（E5564）」の第3相試験を継続”. ニュースリリース. 2010年11月3日閲覧。

参考文献

笹月健彦監訳 K.マーフィー他著: Janeway's 免疫生物学原書第7版 ISBN 978-4-524-25319-7

wiki en

[Wiki en表示]

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. TLR 4 has also been designated as CD284 (cluster of differentiation 284).

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 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

Interactions

TLR 4 has been shown to interact with:

Lymphocyte antigen 96,^[4]^[5]
Myd88,^[6]^[7]^[8]^[9] and
TOLLIP.^[10]

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]

Clinical significance

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]

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,^[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]

Agonists

Ethanol
Morphine-3-glucuronide (inactive at opioid receptors, so selective for TLR4 activation)^[16]^[24]
Morphine^[24]
Oxycodone^[24]
Levorphanol^[24]
Pethidine^[24]
Glucuronoxylomannan from Cryptococcus^[25]^[26]
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.^[27]
Lipopolysaccharides (LPS)^[28]
Carbamazepine^[29]
Oxcarbazepine^[29]

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.^[30]
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^[29]
Ketotifen^[29]
Cyclobenzaprine^[29]
Mianserin^[29]
Imipramine^[29]

References

^ 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. //www.ncbi.nlm.nih.gov/pmc/articles/PMC18464/.
^ 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.
^ "Entrez Gene: TLR 4 toll-like receptor 4". http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=7099.
^ 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. //www.ncbi.nlm.nih.gov/pmc/articles/PMC2193086/.
^ 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. 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.
^ 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. //www.ncbi.nlm.nih.gov/pmc/articles/PMC2942958/.
^ 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 85: 207–19. doi:10.1016/S0074-7742(09)85016-2. 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. //www.ncbi.nlm.nih.gov/pmc/articles/PMC2795035/.
^ 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. //www.ncbi.nlm.nih.gov/pmc/articles/PMC3025088/.
^ ^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. //www.ncbi.nlm.nih.gov/pmc/articles/PMC2783351/.
^ ^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. //www.ncbi.nlm.nih.gov/pmc/articles/PMC2588470/.
^ 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. //www.ncbi.nlm.nih.gov/pmc/articles/PMC2783238/.
^ 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. //www.ncbi.nlm.nih.gov/pmc/articles/PMC2854318/.
^ 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. //www.ncbi.nlm.nih.gov/pmc/articles/PMC2788078/.
^ 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 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. //www.ncbi.nlm.nih.gov/pmc/articles/PMC2080825/.
^ 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. //www.ncbi.nlm.nih.gov/pmc/articles/PMC2872682/.
^ 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.

External links

Toll-Like+Receptor+4 at the US National Library of Medicine Medical Subject Headings (MeSH)

UpToDate Contents

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1. Toll様受容体：疾患および治療における役割 toll like receptors roles in disease and therapy
2. 肥満細胞：表面受容体とシグナル伝達 mast cells surface receptors and signal transduction
3. アテローム性動脈硬化症の病因 pathogenesis of atherosclerosis
4. 自然免疫系の概要 an overview of the innate immune system
5. 無症候性細菌尿のある成人に対するアプローチ approach to the adult with asymptomatic bacteriuria

English Journal

Anti-β(2)GPI/β(2)GPI induced TF and TNF-α expression in monocytes involving both TLR4/MyD88 and TLR4/TRIF signaling pathways.

Xie H, Zhou H, Wang H, Chen D, Xia L, Wang T, Yan J.SourceDepartment of Clinical Laboratory and Hematology, School of Medical Science and Laboratory Medicine of Jiangsu University, Zhenjiang, Jiangsu 212013, PR China.
Molecular immunology.Mol Immunol.2013 Mar;53(3):246-54. doi: 10.1016/j.molimm.2012.08.012. Epub 2012 Sep 8.
Our previous study demonstrated that Toll-like receptor 4 (TLR4) could act as a co-receptor with annexin A2 (ANX2) mediating anti-β2-glycoprotein I/β2-glycoprotein I (anti-β(2)GPI/β(2)GPI)-induced tissue factor (TF) expression in human acute monocytic leukemia cell line THP-1. In the current stu
PMID 22964479

The nutritional supplement Active Hexose Correlated Compound (AHCC) has direct immunomodulatory actions on intestinal epithelial cells and macrophages involving TLR/MyD88 and NF-κB/MAPK activation.

Daddaoua A, Martínez-Plata E, Ortega-González M, Ocón B, Aranda CJ, Zarzuelo A, Suárez MD, de Medina FS, Martínez-Augustin O.SourceDepartment of Environmental Protection, Consejo Superior de Investigaciones Científicas, C/ Profesor Albareda 1, E-18008 Granada, Spain.
Food chemistry.Food Chem.2013 Feb 15;136(3-4):1288-95. doi: 10.1016/j.foodchem.2012.09.039. Epub 2012 Sep 23.
Active Hexose Correlated Compound (AHCC) is an immunostimulatory nutritional supplement. AHCC effects and mechanism of action on intestinal epithelial cells or monocytes are poorly described. AHCC was added to the culture medium of intestinal epithelial cells (IEC18 and HT29 cells) and monocytes (TH
PMID 23194525

Japanese Journal

Suppression of experimental arthritis with self-assembling glycol-split heparin nanoparticles via inhibition of TLR4-NF-κB signaling.

Babazada Hasan,Yamashita Fumiyoshi,Hashida Mitsuru
Journal of controlled release 194, 295-300, 2014-11-28
… It has been recently shown that Toll-like receptor4 mediated nuclear factor κB (TLR4-NF-κB) signaling plays a critical role in the pathogenesis of rheumatoid arthritis mediated by pro-inflammatory cytokines in arthritic synovium. … Here we evaluate the therapeutic potential of glycol-split non-anticoagulant heparin/d-erythro-sphingosine nanoparticles (NAHNPs), which have shown strong inhibitory effect against TLR4 induced inflammation, in an experimental arthritis model. …
NAID 120005512274

Self-assembling lipid modified glycol-split heparin nanoparticles suppress lipopolysaccharide-induced inflammation through TLR4-NF-κB signaling.

Babazada Hasan,Yamashita Fumiyoshi,Yanamoto Shinya,Hashida Mitsuru
Journal of controlled release 194, 332-340, 2014-11-28
Self-assembling heparin nanoparticles have attracted much attention as promising drug carriers for various drugs, genes and imaging agents. In the present investigation, we found that heparin nanopart …
NAID 120005512273

腸内細菌と慢性肝疾患 (第1土曜特集腸内細菌と疾患)

角田圭雄,伊藤義人
医学のあゆみ 251(1), 81-84, 2014-10-04
NAID 40020212342

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★リンクテーブル★

リンク元	「Toll様受容体4」
関連記事	「TL」

「Toll様受容体4」

Toll-like receptor 4
	; PDB rendering based on 2z64.
Available structures
PDB	Ortholog search: PDBe, RCSB
List of PDB id codes
	2Z62, 2Z63, 2Z65, 2Z66, 3FXI, 3UL7, 3UL8, 3UL9, 3ULA, 4G8A
Identifiers
Symbols	TLR4; ARMD10; CD284; TLR-4; TOLL
External IDs	OMIM: 603030 MGI: 96824 HomoloGene: 41317 ChEMBL: 5255 GeneCards: TLR4 Gene
Gene Ontology
Molecular function	• lipopolysaccharide binding; • lipopolysaccharide receptor activity; • receptor activity; • transmembrane signaling receptor activity; • protein binding; • phosphatidylinositol 3-kinase binding;
Cellular component	• cytoplasm; • plasma membrane; • integral to plasma membrane; • external side of plasma membrane; • endosome 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; • skeletal muscle contraction; • immune response; • response to oxidative stress; • 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; • detection of lipopolysaccharide; • response to progesterone stimulus; • interferon-gamma production; • 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 3 signaling pathway; • toll-like receptor 4 signaling pathway; • TRIF-dependent toll-like receptor 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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英: Toll-like receptor 4、TLR4
関: Toll様レセプター4

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[1] Tidswell M, Tillis W, Larosa SP, Lynn M, Wittek AE, Kao R, Wheeler J, Gogate J, Opal SM; Eritoran Sepsis Study Group (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.

[2] エーザイ (2010年3月26日). “重症敗血症治療剤「エリトラン（E5564）」の第3相試験を継続”. ニュースリリース. 2010年11月3日閲覧。

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[pmid19833175-16] 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. //www.ncbi.nlm.nih.gov/pmc/articles/PMC2795035/.

[pmid21081778-17] 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.

[pmid20974246-18] 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. //www.ncbi.nlm.nih.gov/pmc/articles/PMC3025088/.

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[pmid20178837-22] 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. //www.ncbi.nlm.nih.gov/pmc/articles/PMC2854318/.

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[pmid19679181-24] ^ ^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. //www.ncbi.nlm.nih.gov/pmc/articles/PMC2788078/.

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[pmid20381591-29] ^ ^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. //www.ncbi.nlm.nih.gov/pmc/articles/PMC2872682/.

[30] 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.

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TLR4