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Toll-like receptor 5, also known as TLR5, is a protein which in humans is encoded by the TLR5 gene.[1] It is a member of the toll-like receptor (TLR) family. TLR5 is known to recognize bacterial flagellin from invading mobile bacteria.[2] Recent studies have also shown that functioning of TLR5 is likely related to osteoclastogenesis an bone loss.[3] Abnormal TLR5 functioning is related to the onset of gastric, cervical, endometrial and ovarian cancers.[4][5]

Signaling pathway and regulation[edit]

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[6]. The recruitment of MyD88 leads to subsequent activation of IRAK4, IRAK1, TRAF6, and eventually IκB kinases[7][8]. Activation of IκB kinases contributes to the nuclear localization of NF-κB and therefore initiate 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[9].

Recent study has identified Caveolin-1 as a potential regulator of TLR5 expression[10]. In contrast to the diminished 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 decrease in the absence of Caveolin-1 expression[10]. It is hypothesized that the Caveolin-1 directly interacts with TLR5 to increase its half-life and hence increases the level of TLR5.

Clinical significance[edit]

Inflammatory Bowel Disease[edit]

TLR5 may play a role in Inflammatory Bowel Disease (IBD). 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.[11]

Osteoclastogenesis and bone loss[edit]

Bone loss and osteoclastogenesis are induced by inflammation in infectious and autoimmune diseases[12]. Recent study has identified TLR5 as a novel mediator in the process of inflammation-induced bone loss and osteoclastogenesis. Flagellin, 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, robust osteoclast formation, and bone loss[12]. This cascade is absent in TLR5 knockout mice model[12].

Cancer[edit]

Gastric cancer[edit]

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[13]. 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[14]. However, TLR5 interaction with H. pylori only induces weak receptor activation. The inflammatory response induced by TLR5 during H. pylori is also considered to be possibly flagellin independent[13]. In addition to inflammation induction, TLR5 is also shown to enhance gastric cancer cell proliferation through a ERK-dependent pathway[15]. This is supported by the increased level of TLR5 expression from normal mucosa to gastric dysplasia[16].

Cervical cancer[edit]

TLR5 is suggested to be possibly involved in HPV induced inflammation and subsequent cervical neoplasia formation[17]. 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[18]. However, the exact mechanism of interaction between TLR5 and HPV is not known.

Ovarian cancer[edit]

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[19].

References[edit]

  1. ^ 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.
  2. ^ Miao, Edward A.; Andersen-Nissen, Erica; Warren, Sarah E.; Aderem, Alan (2007-08-10). "TLR5 and Ipaf: dual sensors of bacterial flagellin in the innate immune system". Seminars in Immunopathology. 29 (3): 275–288. doi:10.1007/s00281-007-0078-z. ISSN 1863-2297.
  3. ^ Kassem, Ali; Henning, Petra; Kindlund, Bert; Lindholm, Catharina; Lerner, Ulf H. (2015-11-01). "TLR5, a novel mediator of innate immunity-induced osteoclastogenesis and bone loss". The FASEB Journal. 29 (11): 4449–4460. doi:10.1096/fj.15-272559. ISSN 0892-6638. PMID 26207027.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  4. ^ Castaño-Rodríguez, Natalia; Kaakoush, Nadeem O.; Mitchell, Hazel M. (2014-01-01). "Pattern-recognition receptors and gastric cancer". Tumor Immunity. 5: 336. doi:10.3389/fimmu.2014.00336. PMC 4105827. PMID 25101079.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  5. ^ 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.
  6. ^ Gewirtz, A. T.; Navas, T. A.; Lyons, S.; Godowski, P. J.; Madara, J. L. (2001-08-15). "Cutting edge: bacterial flagellin activates basolaterally expressed TLR5 to induce epithelial proinflammatory gene expression". Journal of Immunology (Baltimore, Md.: 1950). 167 (4): 1882–1885. ISSN 0022-1767. PMID 11489966.
  7. ^ Gohda, Jin; Matsumura, Takayuki; Inoue, Jun-ichiro (2004-09-01). "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 (Baltimore, Md.: 1950). 173 (5): 2913–2917. ISSN 0022-1767. PMID 15322147.
  8. ^ Moors, M. A.; Li, L.; Mizel, S. B. (2001-07-01). "Activation of interleukin-1 receptor-associated kinase by gram-negative flagellin". Infection and Immunity. 69 (7): 4424–4429. doi:10.1128/IAI.69.7.4424-4429.2001. ISSN 0019-9567. PMC 98515. PMID 11401982.
  9. ^ Miao, Edward A.; Andersen-Nissen, Erica; Warren, Sarah E.; Aderem, Alan (2007-08-10). "TLR5 and Ipaf: dual sensors of bacterial flagellin in the innate immune system". Seminars in Immunopathology. 29 (3): 275–288. doi:10.1007/s00281-007-0078-z. ISSN 1863-2297.
  10. ^ a b Lim, Jae Sung; Nguyen, Kim Cuc Thi; Han, Jung Min; Jang, Ik-Soon; Fabian, Claire; Cho, Kyung A. (2015-12-31). "Direct Regulation of TLR5 Expression by Caveolin-1". Molecules and Cells. 38 (12): 1111–1117. doi:10.14348/molcells.2015.0213. ISSN 0219-1032. PMC 4697003. PMID 26615831.
  11. ^ "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. Oct 2009. PMID 20083854. {{cite journal}}: |first2= missing |last2= (help); |first3= missing |last3= (help); More than one of author-name-list parameters specified (help)
  12. ^ a b c Kassem, Ali; Henning, Petra; Kindlund, Bert; Lindholm, Catharina; Lerner, Ulf H. (2015-11-01). "TLR5, a novel mediator of innate immunity-induced osteoclastogenesis and bone loss". The FASEB Journal. 29 (11): 4449–4460. doi:10.1096/fj.15-272559. ISSN 0892-6638. PMID 26207027.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  13. ^ a b Castaño-Rodríguez, Natalia; Kaakoush, Nadeem O.; Mitchell, Hazel M. (2014-01-01). "Pattern-recognition receptors and gastric cancer". Frontiers in Immunology. 5: 336. doi:10.3389/fimmu.2014.00336. ISSN 1664-3224. PMC 4105827. PMID 25101079.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  14. ^ Smith, Michael F.; Mitchell, Anastasia; Li, Guolian; Ding, Song; Fitzmaurice, Ann Marie; Ryan, Kieran; Crowe, Sheila; Goldberg, Joanna B. (2003-08-29). "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): 32552–32560. doi:10.1074/jbc.M305536200. ISSN 0021-9258. PMID 12807870.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  15. ^ Song, Eun-Jung; Kang, Min-Jung; Kim, Yong-Seok; Kim, Sun-Moon; Lee, Sang-Eok; Kim, Chang-Hwan; Kim, Dong-Jae; Park, Jong-Hwan (2011-07-01). "Flagellin promotes the proliferation of gastric cancer cells via the Toll-like receptor 5". International Journal of Molecular Medicine. 28 (1): 115–119. doi:10.3892/ijmm.2011.656. ISSN 1791-244X. PMID 21455558.
  16. ^ Pimentel-Nunes, Pedro; Afonso, Luís; Lopes, Paula; Roncon-Albuquerque, Roberto; Gonçalves, Nádia; Henrique, Rui; Moreira-Dias, Luís; Leite-Moreira, Adelino F.; Dinis-Ribeiro, Mário (2011-09-01). "Increased expression of toll-like receptors (TLR) 2, 4 and 5 in gastric dysplasia". Pathology oncology research: POR. 17 (3): 677–683. doi:10.1007/s12253-011-9368-9. ISSN 1532-2807. PMID 21455638.
  17. ^ 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.
  18. ^ 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.
  19. ^ 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: CII. 58 (9): 1375–1385. doi:10.1007/s00262-008-0650-y. ISSN 1432-0851. PMID 19184006.
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