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Tlr7- Cluster of Differentiation 287

Toll-like receptor 7 (TLR7), is an immune gene possessed by humans, other mammals and additionally in avian species playing a significant role in initiating antiviral immune responses. It belongs to the evolutionarily conserved Toll-like receptor family. The TLR7 sequence encodes a 1049 amino acid protein with a calculated molecular weight of 121 kDa. Like all other members of the TLR family, TLR7 contain an ectodomain with multiple leucine-rich repeats (LRRs) and a cytoplasmic domain homologous to that of the human interleukin-1 (IL-1) receptor. TLR7 is most closely related to TLR8 and TLR9 with 43% and 36% overall amino acid sequence identity, respectively and thus along with TLR8 and TLR9 constitutes a new sub-family of the TLRs.

In vivo, TLR7 mRNA is expressed in lung, placenta, spleen, lymph node, and tonsil. TLR7 mRNA expression is highest in monocytes, B cells, and DC. In vitro, TLR7 mRNA expression is upregulated in THP-1 cells upon PMA-induced differentiation. TLR7 is highly upregulated by exposure to IL-6 and to a slightly lesser extent by autocrine IFN-?, IL-1?. TLR7 mRNA expression in THP-1 cells is elevated after exposure to both Gram-positive and Gram-negative bacteria. Ex vivo, expression of TLR7 is elevated after exposure to both Gram-positive and Gram-negative bacteria in monocytes and to a greater degree in granulocytes. Like TLR3, it appears that TLR7 may be localized intracellularly (1, 2). In humans, TLR7 is expressed on a restricted range of cell types with the highest abundance found on plasmacytoid dendritic cells and B cells.

TLR7 is activated by infections with single-stranded RNA viruses, including influenza virus and vesicular stomatitis virus (VSV). Stimulation of TLR7 with the viral nucleic acids, causes a type I IFN response and secretion of a large quantity of IFN? and the production of inflammatory cytokines [including IFN-alpha, IFN-beta, interleukin-6 (IL-6), IL-12, tumour necrosis factor-alpha (TNF-alpha)]. TLR7 activation also mediates up-regulation of costimulatory molecules (CD40, CD80, CD86), major histocompatibilty complex molecules and chemokine receptors (CCR7) (3). Two signaling pathways of TLR7 are thought to induce inflammatory cytokine expression: the MyD88- IRAK1-TRAF6-IRF5 pathway and the MyD88-TRAF6-TAK1-MAPK/IKK-AP-1/NF-?B pathway.(4) Following nucleic acid recognition, TLR7 recruit the TIR-domain

containing adapter called MyD88. MyD88 forms a complex with members of IRAK family

(IRAK1 and IRAK4) and TRAF6, which in turn activates TAK1 and results in the activation of NF-?B. In addition to single-stranded RNA, the synthetic imidazoquinoline, imiquimod, a low molecular weight immune response modifier, activates TLR7 in both humans and mice, whereas its derivative resiquimod (R-848) activates TLR7 in humans. Both imiquimod and R-848 elicit robust anti-viral and anti-tumor immune responses in vivo, which correlate with a strong induction of type I IFNs. As a consequence of this activity, imiquimod is used for the treatment of external genital warts caused by human Papillomavirus. (5) TLR7 has been implicated in recognizing guanosine and uracil-rich single-stranded(ss) RNA such as the U5 region of human immunodeficiency virus type 1 RNA and influenza U-rich ssRNA, leading to up-regulation of IFN-alpha.

Reference:

1. Heine, H. & E. Lein (2003) Int. Arch. Allergy Immunol. 130:180.

2. Dunne, A. & L.A.J. O'Neill (2003) Sci. STKE 2003:re3.

3. Victoria J Volume 114 Issue 4 Page 507-521, April 2005

4. Myeong Sup Lee Annual Review of BiochemistryVol. 76: 447-480, 2007.

5. Annett Schoenemeyer J. Biol. Chem., Vol. 280, Issue 17, 17005-17012, April 29, 2005.

About the Author

IMGENEX India Pvt Ltd. the only biotech company in Orissa and one of its kinds in Eastern India. IMGENEX India started in Oct as an outsourcing branch of IMGENEX Corporation, San Diego, USA. Find out more information about Toll-like receptors .

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