• integral component of membrane • membrane • plasma membrane
Biological process
• positive regulation of cytokine production • signal transduction • positive regulation of toll-like receptor signaling pathway • defense response to bacterium • MyD88-dependent toll-like receptor signaling pathway • regulation of cytokine secretion • toll-like receptor 5 signaling pathway • immune system process • positive regulation of interleukin-8 production • cellular response to mechanical stimulus • innate immune system • inflammatory response
Sources:Amigo / QuickGO
Orthologs
Species
Human
Mouse
Entrez
7100
53791
Ensembl
ENSG00000187554
ENSMUSG00000079164
UniProt
O60602
Q9JLF7
RefSeq (mRNA)
NM_003268
NM_016928
RefSeq (protein)
NP_003259
NP_058624
Location (UCSC)
Chr 1: 223.11 – 223.14 Mb
Chr 1: 182.95 – 182.98 Mb
PubMed search
[3]
[4]
Wikidata
View/Edit Human
View/Edit Mouse
Toll-like receptor 5, also known as TLR5, is a protein which in humans is encoded by the TLR5 gene.[5] It is a member of the toll-like receptor (TLR) family. TLR5 is known to recognize bacterial flagellin from invading mobile bacteria.[6] It has been shown to be involved in the onset of many diseases, which includes Inflammatory bowel disease.[7] Recent studies have also shown that malfunctioning of TLR5 is likely related to osteoclastogenesis and bone loss.[8] Abnormal TLR5 functioning is related to the onset of gastric, cervical, endometrial and ovarian cancers.[9][10]
Contents
1Function
2Signaling pathway and regulation
3Clinical significance
3.1Inflammatory bowel disease
3.2Osteoclastogenesis and bone loss
3.3Cancer
3.3.1Gastric cancer
3.3.2Cervical cancer
3.3.3Ovarian cancer
4References
5Further reading
6External links
Function
The TLR family 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. TLR5 is expressed on both immune and non-immune cells.[11] TLR5 recognizes bacterial flagellin, a principal component of bacterial flagella and a virulence factor. The activation of this receptor mobilizes the nuclear factor NF-κB and stimulates tumor necrosis factor-alpha production.[12]
TLR5 recognizes flagellin,[13] which is the protein monomer that makes up the filament of bacterial flagella, found on nearly all motile bacteria. There are highly conserved regions in the flagellin protein among all bacteria, facilitating the recognition of flagellin by a germ-line encoded receptor such as TLR5.[14] However, some Proteobacteria flagella have acquired mutations preventing their recognition by TLR5.[15]
Signaling pathway and regulation
The TLR5 signaling cascade is commonly triggered by the binding of bacterial flagellum to TLR5 on the cell surface. Binding of flagellum induces the dimerization of TLR5, which in turn recruits MyD88.[16] The recruitment of MyD88 leads to subsequent activation of IRAK4, IRAK1, TRAF6, and eventually IκB kinases.[17][18] Activation of IκB kinases contributes to the nuclear localization of NF-κB (a proinflammatory cytokine). NF-κB induces many downstream gene expressions, which initiates the canonical proinflammatory pathway. This TLR5/flagellum interaction results in different responses in difference cell types. In epithelial cells, binding of flagellum to TLR5 induces IL8 production. In human monocytes and dendritic cells, this interaction results in the secretion of proinflammatory cytokines such as TNF.[6]
Recent study has identified Caveolin-1 as a potential regulator of TLR5 expression.[19] In contrast to the decreased TLR4 level in senescent cells, TLR5 expression maintains relative stable during the aging process, which is correlated with the high level of Caveolin-1 in aging cells. Data from Caveolin-1 knockout mice demonstrated that TLR5 expression significantly decreases in the absence of Caveolin-1 expression in aging cells.[19] It is hypothesized that the Caveolin-1 directly interacts with TLR5 to stabilize it and hence increases the level of TLR5.
Clinical significance
Inflammatory bowel disease
TLR5 may play a role in inflammatory bowel disease (IBD). TLR5-deficient mice develop spontaneous colitis [20] and metabolic syndrome which are associated with altered gut microbiota.[21]
Statistically significant lower levels of TLR5 expression have been found in patients exhibiting moderate to severe ulcerative colitis (UC). In these patients, lower TLR5 mRNA levels were found along with decreased immunoreactivity of TLR5 in the inflamed mucosa of UC patients.[7]
Osteoclastogenesis and bone loss
Bone loss and osteoclastogenesis are induced by inflammation in infectious and autoimmune diseases.[8] A recent study has identified TLR5 as a novel mediator in the process of inflammation-induced bone loss and osteoclastogenesis. Flagellin, which is a TLR5-activating ligand, is present in synovial fluid from patients with rheumatoid arthritis. Activation of TLR5 in these patients leads to subsequent activation of receptor activator of NF-kB ligand (RANKL). Activation of RANKL leads to increased expression of osteoclastic genes. Activation of these genes results in robust osteoclast formation and bone loss.[8] This process is absent in TLR5 knockout mice model.[8]
Cancer
Gastric cancer
Chronic inflammation in GI tract has been known to increase the risk of gastric cancer, with H. pylori being one of the most common resources of infection.[9] TLR5 is an essential factor in inducing inflammatory response to H. pylori infection. During infection, expression and ligation of TLR5 and TLR2 are required for the activation of proinflammatory cytokines such as NF-κB.[22] However, TLR5 interaction with H. pylori only induces weak TLR5 activation. The inflammatory response induced by TLR5 during H. pylori is also considered to be possibly flagellin independent. This suggests that an unknown H. pylori factor is responsible for this response[9] In addition to inflammation induction, TLR5 is also shown to enhance gastric cancer cell proliferation through a ERK-dependent pathway.[23] This is supported by the increased level of TLR5 expression from normal gastric mucosa to gastric cancer cells.[24]
Cervical cancer
TLR5 is suggested to be possibly involved in HPV induced inflammation and subsequent cervical neoplasia formation.[25] TLR5 is generally absent in normal cervical squamous epithelium. However, a gradually increased level of TLR5 expression has been detected in low-grade cervical intraepithelial neoplasia (CIN), high grade CIN, and invasive cervical cancer.[26] However, the exact mechanism of interaction between TLR5 and HPV is not known.
Ovarian cancer
It has been reported that TLR5 expression is detected in both ovarian epithelium and ovarian cancer cell lines but not in ovarian stroma, suggesting a possible role of TLR5 in inflammation induced ovarian cancer onset.[27]
References
^ abcGRCh38: Ensembl release 89: ENSG00000187554 - Ensembl, May 2017
^ abcGRCm38: Ensembl release 89: ENSMUSG00000079164 - Ensembl, May 2017
^"Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^"Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^Rock FL, Hardiman G, Timans JC, Kastelein RA, Bazan JF (Jan 1998). "A family of human receptors structurally related to Drosophila Toll". Proceedings of the National Academy of Sciences of the United States of America. 95 (2): 588–93. doi:10.1073/pnas.95.2.588. PMC 18464. PMID 9435236.
^ abMiao EA, Andersen-Nissen E, Warren SE, Aderem A (Sep 2007). "TLR5 and Ipaf: dual sensors of bacterial flagellin in the innate immune system". Seminars in Immunopathology. 29 (3): 275–88. doi:10.1007/s00281-007-0078-z. PMID 17690885.
^ abStanislawowski M, Wierzbicki PM, Golab A, Adrych K, Kartanowicz D, Wypych J, Godlewski J, Smoczynski M, Kmiec Z (Oct 2009). "Decreased Toll-like receptor-5 (TLR-5) expression in the mucosa of ulcerative colitis patients". Journal of Physiology and Pharmacology. 60 Suppl 4: 71–5. PMID 20083854.
^ abcdKassem A, Henning P, Kindlund B, Lindholm C, Lerner UH (Nov 2015). "TLR5, a novel mediator of innate immunity-induced osteoclastogenesis and bone loss". FASEB Journal. 29 (11): 4449–60. doi:10.1096/fj.15-272559. PMID 26207027.
^ abcCastaño-Rodríguez N, Kaakoush NO, Mitchell HM (2014-01-01). "Pattern-recognition receptors and gastric cancer". Frontiers in Immunology. 5: 336. doi:10.3389/fimmu.2014.00336. PMC 4105827. PMID 25101079.
^Husseinzadeh N, Davenport SM (Nov 2014). "Role of toll-like receptors in cervical, endometrial and ovarian cancers: a review". Gynecologic Oncology. 135 (2): 359–63. doi:10.1016/j.ygyno.2014.08.013. PMID 25135000.
^Sharma N, Akhade AS, Qadri A (Apr 2013). "Sphingosine-1-phosphate suppresses TLR-induced CXCL8 secretion from human T cells". Journal of Leukocyte Biology. 93 (4): 521–8. doi:10.1189/jlb.0712328. PMID 23345392.
^"Entrez Gene: TLR5 toll-like receptor 5".
^Hayashi F, Smith KD, Ozinsky A, Hawn TR, Yi EC, Goodlett DR, Eng JK, Akira S, Underhill DM, Aderem A (Apr 2001). "The innate immune response to bacterial flagellin is mediated by Toll-like receptor 5". Nature. 410 (6832): 1099–103. doi:10.1038/35074106. PMID 11323673.
^Smith KD, Andersen-Nissen E, Hayashi F, Strobe K, Bergman MA, Barrett SL, Cookson BT, Aderem A (Dec 2003). "Toll-like receptor 5 recognizes a conserved site on flagellin required for protofilament formation and bacterial motility". Nature Immunology. 4 (12): 1247–53. doi:10.1038/ni1011. PMID 14625549.
^Andersen-Nissen E, Smith KD, Strobe KL, Barrett SL, Cookson BT, Logan SM, Aderem A (Jun 2005). "Evasion of Toll-like receptor 5 by flagellated bacteria". Proceedings of the National Academy of Sciences of the United States of America. 102 (26): 9247–52. doi:10.1073/pnas.0502040102. PMC 1166605. PMID 15956202.
^Gohda J, Matsumura T, Inoue J (Sep 2004). "Cutting edge: TNFR-associated factor (TRAF) 6 is essential for MyD88-dependent pathway but not toll/IL-1 receptor domain-containing adaptor-inducing IFN-beta (TRIF)-dependent pathway in TLR signaling". Journal of Immunology. 173 (5): 2913–7. doi:10.4049/jimmunol.173.5.2913. PMID 15322147.
^Moors MA, Li L, Mizel SB (Jul 2001). "Activation of interleukin-1 receptor-associated kinase by gram-negative flagellin". Infection and Immunity. 69 (7): 4424–9. doi:10.1128/IAI.69.7.4424-4429.2001. PMC 98515. PMID 11401982.
^ abLim JS, Nguyen KC, Han JM, Jang IS, Fabian C, Cho KA (Dec 2015). "Direct Regulation of TLR5 Expression by Caveolin-1". Molecules and Cells. 38 (12): 1111–7. doi:10.14348/molcells.2015.0213. PMC 4697003. PMID 26615831.
^Singh V, Yeoh BS, Carvalho F, Gewirtz AT, Vijay-Kumar M (July 2015). "Proneness of TLR5 deficient mice to develop colitis is microbiota dependent". Gut Microbes. 6: 279–83. doi:10.1080/19490976.2015.1060390. PMC 4615783. PMID 26067589.
^Vijay-Kumar M, Aitken JD, Carvalho FA, Cullender TC, Mwangi S, Srinivasan S, Sitaraman SV, Knight R, Ley RE, Gewirtz AT (April 2010). "Metabolic syndrome and altered gut microbiota in mice lacking Toll-like receptor 5". Science. 328: 228–31. doi:10.1126/science.1179721. PMC 4714868. PMID 20203013.
^Smith MF, Mitchell A, Li G, Ding S, Fitzmaurice AM, Ryan K, Crowe S, Goldberg JB (Aug 2003). "Toll-like receptor (TLR) 2 and TLR5, but not TLR4, are required for Helicobacter pylori-induced NF-kappa B activation and chemokine expression by epithelial cells". The Journal of Biological Chemistry. 278 (35): 32552–60. doi:10.1074/jbc.M305536200. PMID 12807870.
^Song EJ, Kang MJ, Kim YS, Kim SM, Lee SE, Kim CH, Kim DJ, Park JH (Jul 2011). "Flagellin promotes the proliferation of gastric cancer cells via the Toll-like receptor 5". International Journal of Molecular Medicine. 28 (1): 115–9. doi:10.3892/ijmm.2011.656. PMID 21455558.
^Pimentel-Nunes P, Afonso L, Lopes P, Roncon-Albuquerque R, Gonçalves N, Henrique R, Moreira-Dias L, Leite-Moreira AF, Dinis-Ribeiro M (Sep 2011). "Increased expression of toll-like receptors (TLR) 2, 4 and 5 in gastric dysplasia". Pathology Oncology Research. 17 (3): 677–83. doi:10.1007/s12253-011-9368-9. PMID 21455638.
^Husseinzadeh, Nader; Davenport, Sara Madison (2014-11-01). "Role of toll-like receptors in cervical, endometrial and ovarian cancers: a review". Gynecologic Oncology. 135 (2): 359–363. doi:10.1016/j.ygyno.2014.08.013. ISSN 1095-6859. PMID 25135000.
^Lee, Jeong-Won; Choi, Jung-Joo; Seo, Eun Sung; Kim, Mi Jin; Kim, Woo Young; Choi, Chel Hun; Kim, Tae-Joong; Kim, Byoung-Gie; Song, Sang Yong (2007-11-01). "Increased toll-like receptor 9 expression in cervical neoplasia". Molecular Carcinogenesis. 46 (11): 941–947. doi:10.1002/mc.20325. ISSN 0899-1987. PMID 17440926.
^Zhou, Mingfu; McFarland-Mancini, Molly M.; Funk, Holly M.; Husseinzadeh, Nader; Mounajjed, Taofic; Drew, Angela F. (2009-09-01). "Toll-like receptor expression in normal ovary and ovarian tumors". Cancer Immunology, Immunotherapy. 58 (9): 1375–1385. doi:10.1007/s00262-008-0650-y. ISSN 1432-0851. PMID 19184006.
Further reading
Hayashi F, Smith KD, Ozinsky A, Hawn TR, Yi EC, Goodlett DR, Eng JK, Akira S, Underhill DM, Aderem A (Apr 2001). "The innate immune response to bacterial flagellin is mediated by Toll-like receptor 5". Nature. 410 (6832): 1099–103. doi:10.1038/35074106. PMID 11323673.
Lien E, Ingalls RR (Jan 2002). "Toll-like receptors". Critical Care Medicine. 30 (1 Suppl): S1–11. doi:10.1097/00003246-200201001-00001. PMID 11782555.
External links
Toll-Like+Receptor+5 at the US National Library of Medicine Medical Subject Headings (MeSH)
v
t
e
Signaling pathway: TLR signaling pathway
Receptor
TLR 4
TLR 1
TLR 2
TLR 6
TLR 5
TLR 10
Other external
CD14
MD2
LBP
Internal
adaptor: MYD88
TRIF
TIRAP
TRAF6
TOLLIP
IRAK1
IRAK4
IRF3
TLR 3
TLR 7
TLR 8
TLR 9
UpToDate Contents
全文を閲覧するには購読必要です。 To read the full text you will need to subscribe.
2. 巨細胞（側頭）動脈炎の病因 pathogenesis of giant cell temporal arteritis
3. 慢性肉芽腫性疾患：病因、臨床症状、および診断 chronic granulomatous disease pathogenesis clinical manifestations and diagnosis
4. サルモネラ胃腸炎の病因 pathogenesis of salmonella gastroenteritis
5. 全身性エリテマトーデスの疫学および病因 epidemiology and pathogenesis of systemic lupus erythematosus
English Journal
Clostridium difficile flagellin stimulates toll-like receptor 5, and toxin B promotes flagellin-induced chemokine production via TLR5.
Yoshino Y, Kitazawa T, Ikeda M, Tatsuno K, Yanagimoto S, Okugawa S, Yotsuyanagi H, Ota Y.SourceDepartment of Infectious Diseases, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan; Department of Medicine, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi-ku, Tokyo 173-8606, Japan.
Life sciences.Life Sci.2013 Feb 27;92(3):211-7. doi: 10.1016/j.lfs.2012.11.017. Epub 2012 Dec 19.
AIMS: Clostridium difficile is an important pathogen in nosocomial infections. Although C. difficile toxins are considered to be major virulence factors, pathogenesis of C. difficile associated diseases remains to be determined. In this study, we investigated whether C. difficile flagellin is involv
Vaccination with recombinant FimH fused with flagellin enhances cellular and humoral immunity against urinary tract infection in mice.
Asadi Karam MR, Oloomi M, Mahdavi M, Habibi M, Bouzari S.SourceDepartment of Molecular Biology, Pasteur Institute of Iran, Pasteur Ave., Tehran 13164, Iran.
Vaccine.Vaccine.2013 Feb 6;31(8):1210-6. doi: 10.1016/j.vaccine.2012.12.059. Epub 2013 Jan 7.
Urinary tract infection (UTI) caused by Uropathogenic Escherichia coli (UPEC) is one of the most common infections in the world. Despite extensive efforts, a vaccine that confers protection against UTIs in human is currently lacking. In this study, the ability of flagellin (FliC), a Toll-like recept
Detection of flagellin by interaction with human recombinant TLR5 immobilized in liposomes.
Olguín Y, Villalobos P, Carrascosa LG, Young M, Valdez E, Lechuga L, Galindo R.SourceBiotechnology Center, Federico Santa Maria Technical University, Valparaíso, Chile, yusser.olguin@postgrado.usm.cl.
Analytical and bioanalytical chemistry.Anal Bioanal Chem.2013 Feb;405(4):1267-81. doi: 10.1007/s00216-012-6523-4. Epub 2012 Nov 22.
Digestive diseases caused by flagellated bacteria are a huge public health problem worldwide and rapid detection methods are needed for contaminated environments. In this study, we propose a method to detect patterns associated with pathogens based on the properties of the innate immune system. Spec
